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Overview of the Anatomy, Physiology, and

Pharmacology of the Autonomic Nervous System


Erica A. Wehrwein,1 Hakan S. Orer,2 and Susan M. Barman*3

ABSTRACT
Comprised of the sympathetic nervous system, parasympathetic nervous system, and enteric ner-
vous system, the autonomic nervous system (ANS) provides the neural control of all parts of the
body except for skeletal muscles. The ANS has the major responsibility to ensure that the physiolog-
ical integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) in
the face of perturbations exerted by both the external and internal environments. Many commonly
prescribed drugs, over-the-counter drugs, toxins, and toxicants function by altering transmission
within the ANS. Autonomic dysfunction is a signature of many neurological diseases or disorders.
Despite the physiological relevance of the ANS, most neuroscience textbooks offer very limited
coverage of this portion of the nervous system. This review article provides both historical and
current information about the anatomy, physiology, and pharmacology of the sympathetic and
parasympathetic divisions of the ANS. The ultimate aim is for this article to be a valuable re-
source for those interested in learning the basics of these two components of the ANS and to
appreciate its importance in both health and disease. Other resources should be consulted for
a thorough understanding of the third division of the ANS, the enteric nervous system. © 2016
American Physiological Society. Compr Physiol 6:1239-1278, 2016.

Introduction physiology, and pharmacology of the ANS, with an emphasis


on its peripheral components since other articles in Compre-
Pick up any large textbook of neuroscience and in its 1000+ hensive Physiology emphasize central control of autonomic
pages you will find a relatively short chapter (∼25 pages) regulation (37, 69, 125).
devoted to the autonomic nervous system (ANS) and the invol- The ANS has three major divisions: the sympathetic ner-
untary control of visceromotor function. This is in contrast to vous system, the parasympathetic nervous system, and the
the several hundred pages devoted to the somatomotor ner- enteric nervous system. The latter is a nervous system that is
vous system that governs the voluntary control of skeletal intrinsic to the wall of the gastrointestinal tract and works in
muscle contraction to maintain posture and permit locomo- conjunction with the parasympathetic and sympathetic ner-
tion (127, 151, 211, 233, 239). At the 2015 Society for Neuro- vous systems to control digestion. Furness (102) provided
science meeting, none of the scientific sessions over a 5-day a recent review of this division of the ANS. The focus of
meeting had titles that included the word autonomic, sym- this article is limited to the sympathetic and parasympathetic
pathetic, or parasympathetic; and less than 50 oral or poster divisions of the ANS.
presentations included one of these terms in its title. In light of When describing the anatomical, physiological, and phar-
this limited coverage of the ANS in prominent neuroscience macological characteristics of the ANS, it is interesting to
textbooks and scientific meetings, one would think that the compare these to the corresponding characteristics of the
ANS is not a very important component of the neurosciences. somatomotor nervous system. Table 1 compares some of the
To the contrary, the ANS influences the function of nearly major anatomical, physiological, and pharmacological fea-
every organ in the body via its innervation of smooth muscle, tures of these two divisions of the vertebrate nervous system.
cardiac muscle, and glands. In fact, the ANS is responsible for
the control of all innervated organs and tissues except skeletal
* Correspondence to barman@msu.edu
muscles. 1 Department of Physiology, Michigan State University, East Lansing,
Several recent articles within Comprehensive Physiology
Michigan, USA
offer an in-depth coverage of some of the many physiolog- 2 Department of Pharmacology, Koc University School of Medicine,
ical processes regulated by the ANS in both health and dis- Istanbul, Turkey
ease (30,37,69,71,125,149,158,191,194,247). Several older 3 Department of Pharmacology & Toxicology, Michigan State
resources (15, 46, 132, 143, 146, 171, 174, 175, 197, 208, 233) University, East Lansing, Michigan, USA
can also be consulted for detailed reviews on the anatomical Published online, July 2016 (comprehensivephysiology.com)
and functional organization of the ANS. The intent of this DOI: 10.1002/cphy.c150037
particular article is to provide an overview of the anatomy, Copyright © American Physiological Society.

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Table 1 Comparison of the Autonomic and Somatomotor Nervous Systems

Feature Autonomic Somatomotor

Peripheral nervous system Preganglionic and postganglionic neurons, connected in series α-Motor neurons and γ-motor neurons, two
elements parallel populations
Number and location of Two synapses; preganglionic neurons synapse on postganglionic A single synapse; α- and γ-motor neurons
synapses outside of the neurons which then synapse on the effector organ (exception, synapse directly on extrafusal and intrafusal
CNS preganglionic neurons synapse directly on adrenal medulla) fibers in skeletal muscle, respectively
Levels at which neurons Sympathetic: thoracolumbar spinal cord (T1-L2/L4) Brainstem and entire spinal cord
exit CNS Parasympathetic: brainstem and sacral spinal cord (S2-S4)
Location of cell bodies of IML spinal nuclei and brainstem cranial nerve nuclei III, VII, IX, Ventral horn of the spinal cord and cranial
neurons that exit CNS and X nerve nuclei III, IV, VI, VII, XI, and XII
Topographical Yes Yes
organization
Cell body diameter Preganglionic neurons: ∼10-40 μm α-Motor neurons: 50-80 μm;
Postganglionic neurons: ∼15-35 μm γ-motor neurons: ∼30 μm
Axonal diameter Preganglionic neurons: 1-5 μm; α-Motor neurons: 12-22 μm;
Postganglionic neurons: 0.1-2 μm γ-motor neurons: 5-13 μm
Fiber classification Preganglionic neurons: lightly myelinated B fibers or α-Motor neurons: heavily myelinated Aα fibers
unmyelinated C fibers γ-Motor neurons: heavily myelinated Aγ fibers
Postganglionic neurons: unmyelinated C fibers
Axonal conduction Preganglionic neurons: 0.2-15 m/s α-Motor neurons, 70-120 m/s
velocity Postganglionic neurons: 0.2-2 m/s γ-Motor neurons, 15-40 m/s
Effector junction Extensive ramifications and varicosities (containing synaptic Motor end plate, axon terminals embedded in
vesicles) but no specialized region of contact grooves in the surface of the muscle fiber
Effector organs Smooth muscle, cardiac muscle, cardiac conducting fibers, Extrafusal (α-motor neurons) and intrafusal
glands muscle fibers (γ-motor neurons)
Peripheral Acetylcholine: all preganglionic neurons, all parasympathetic Acetylcholine
neurotransmitters∗ postganglionic neurons, some sympathetic postganglionic
neurons (e.g., sweat glands)
Norepinephrine: most postganglionic sympathetic neurons
Epinephrine and norepinephrine: adrenal medulla
Receptor types∗∗ Ganglia: nicotinic cholinergic Neuromuscular junction: nicotinic cholinergic
Effector organ: muscarinic cholinergic and α- and β-adrenergic
Action of neurotransmitter Contraction or relaxation of smooth muscle; increased or Contraction of extrafusal (α-motor neurons)
on effector organ∗∗ decreased rate and force of contraction of cardiac muscle; and intrafusal (γ-motor neurons) fibers in
increased or decreased secretions from glands skeletal muscle
Functions Controls all visceral organs; regulates airway resistance, blood Maintain balance and posture; allow gross
flow, blood pressure, body temperature, digestion, energy and fine movements of the body, limbs,
balance, waste excretion, fluid volume, glandular secretions, digits, and eyes; locomotion; vocalization;
heart rate, immune system, inflammatory processes, salt and swallowing; breathing
water balance, sexual function, urination
Innervation pattern Many effector organs receive dual innervation (both sympathetic Each skeletal muscle fiber is innervated by
and parasympathetic); others receive innervation from either one α-motor neuron; a motor unit is a single
the sympathetic or parasympathetic α-motor neuron and all the muscle fibers it
innervates
Denervation Spontaneous activity of the effector organ may persist; develop Paralysis and atrophy of skeletal muscles
hypersensitivity to neurotransmitters
Control system Primarily unconscious, involuntary control; related to hormonal Primarily conscious, voluntary control;
control unrelated to hormonal control
Motor command and Limbic system, hypothalamus, and brainstem Cerebral cortex, basal ganglia, brainstem,
integration sites in CNS and cerebellum
Sensory input Primarily from visceroceptors (chemoreceptors, baroreceptors, Primarily from exteroceptors and
nociceptors) proprioceptors

∗ SeeTable 7 for neurochemical phenotypes of autonomic nuclei.


∗∗ SeeTable 4 for more details regarding receptor types and effector responses within the autonomic nervous system.
Consult the following references for detailed information about the properties of the somatomotor nervous system: (34,40,54,127,129,151,211,
233, 239).

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At various places throughout this article, we will refer to some disorders (e.g., hypertension, cardiac arrhythmias, congestive
of these key distinguishing features. heart failure, and angina), glaucoma, essential tremor, and
anxiety disorders. Some drugs have been developed for their
action on specific autonomic target organs, such as drugs used
Physiological Relevance of the to treat erectile dysfunction (242). Toxins like nerve gas (an
Autonomic Nervous System organophosphate) interfere with cholinergic transmission not
only at the neuromuscular junction but also on autonomic
The ANS is tightly linked with many behaviors, emotions, effector organs. Some naturally occurring products mimic the
and the immune system (52, 55, 92, 112, 143, 158, 171, 236). action of autonomic neurotransmitters; these include mus-
Some common examples include the altered cardiorespiratory carine from Amanita muscaria, pilocarpine from the rutaceae
responses that are orchestrated during exercise, when attempt- plant family, and atropine or hyoscine from the solanaceae
ing to escape from a threatening environment, when facing plant family.
a fearful situation, during an inflammatory response, or even
when simply moving from a supine to an upright posture. To
meet the metabolic and thermoregulatory demands of differ- Some Historical Milestones in Autonomic
ent situations, the ANS automatically makes adjustments in Neuroscience
regional blood flow and cardiac output, and it also integrates
with the central respiratory network. Also, neuroendocrine Table 2 lists some of the milestones in the history of auto-
physiology is closely linked to autonomic regulation, and nomic neurosciences, including major anatomical, physio-
some autonomic functions (e.g., excretion from the urinary logical, and pharmacological advancements that have shaped
tract and gastrointestinal tract) rely on both the autonomic the field as we know it today. Many books and review articles
(involuntary) and somatic (voluntary) nervous systems for have done an excellent job of providing a historical perspec-
normal physiological behavior. tive of autonomic neuroscience (4, 31, 36, 41, 103, 122, 132,
Although survival might be possible without the sympa- 154,208,223,257).The discoveries described below are a few
thetic nervous system, the ability to adapt to environmental of the key advancements that help explain the important role
stressors and other challenges is severely compromised by the ANS has played in the history of some major develop-
autonomic failure (22, 105, 188). Without an intact parasym- ments in the broad field of the neurosciences.
pathetic nervous system, survival is problematic as one could If autonomic neuroscientists of today were to build their
lose the ability to eliminate wastes and toxins from the body. “family” tree, Walter Holbrook Gaskell (1847-1914) and John
As will be briefly reviewed below under Autonomic Dys- Newport Langley (1852-1925), both of the University of Cam-
function, dysregulation of the ANS is the basis of or a sec- bridge in the United Kingdom, would need to be a positioned
ondary response to many diseases; this includes primary or at a focal point. These individuals are recognized especially
pure autonomic failure, hypertension, diabetes, orthostatic for their work concerning the anatomical organization of the
hypotension, Parkinson Disease, stroke, and sleep disorders ANS. Langley is credited with coining the term autonomic
(48, 75, 119, 186). Also, ongoing studies are now evaluat- nervous system in 1898 when he wrote “I propose the term
ing the efficacy of various medical devices aimed at altering autonomic nervous system for the sympathetic system and
autonomic activity in diseases such as hypertension and heart the allied nervous system of the cranial and sacral nerves, and
failure. These strategies include vagal and carotid sinus nerve for the local nervous system of the gut” (41, 163). In 1921,
stimulation, renal denervation, and device-guided breathing Langley (166) extended his interpretation of the term when
(58, 60, 128, 192, 226, 255, 268-270). Thus, it is important to he wrote, “By this I meant a ‘local’ autonomy. The word
have a solid understanding of the diverse functions of the ANS autonomy indicates without doubt a much greater degree of
to appreciate the pathophysiological basis for many common independence of the central nervous system (CNS), than it
diseases/disorders. is in reality, with the possible exception of innervation of the
In contrast to most general neuroscience textbooks which gastrointestinal canal, but I think that for novel concepts in sci-
include only modest coverage of the ANS, most pharmacol- ence it is also necessary to introduce new terms, even if those
ogy textbooks have multiple chapters devoted to the ANS terms would not represent a precise description of the sub-
(38, 156, 216). This is because many commonly prescribed jects.” Langley also is credited with distinguishing between
drugs, over-the-counter drugs, or toxins and toxicants func- the sympathetic and parasympathetic divisions of the ANS on
tion by altering adrenergic or cholinergic neurotransmission the basis of the opposing actions that these two sets of nerves
within the ANS and/or exert an action downstream on auto- have on many organs. Today this is often mistakenly assumed
nomic target organs and tissues or on nonautonomic effec- to be the rule rather than merely one example of the character
tor targets (186). For example, β-adrenoceptor agonists are of the physiological roles of the two divisions of the ANS.
frequent choices for treatment of asthma and as a growth- Gaskell (106, 107) preferred to use the term “involuntary
promoting food additive for swine, beef cattle, and turkeys nervous system” instead of ANS since this division of the
in the United States (170). Many β-adrenoceptor antagonists nervous system functions independently of consciousness.
are used in the treatment of a wide range of cardiovascular He made important discoveries related to the organization

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Table 2 History of the Autonomic Nervous System

Individual(s) Discovery References

150 AD
Galen First dissection, identification, and description of morphology of peripheral autonomic (4, 118, 154, 231)
nervous system (ANS) including “swellings” (autonomic ganglia); erroneously thought
nerves were purely sensory and hollow, allowing animal spirits to transfer from organ to
organ or chemical “humors”; referred to the concurrent responses of muscle as having
“sympathetic action.”
1400s
Da Vinci Drew precise pictures of human anatomy, including the ANS (1489). (153)
1500s
B Eustachio Credited with the first comprehensive dissection of the ANS in 1555 (albeit not formally (208)
published until 1714); he also discovered the adrenal gland.
1700s
T Willis Anatomic distinction of vagus and intercostalis (sympathetic) fibers; envisioned the (4, 142, 262)
involuntary motion governed by the cerebellum from which vagus and intercostalis
descended; determined that nerves surrounding vessels caused constriction. Also credited
with the use of the term “involuntary nervous system.”
1700s
F Pourfour du Petit Produced what today is known as Horner Syndrome (myosis, ptosis, and enophthalmos) by (4, 209)
sectioning superior sympathetic nerve in a dog. Championed the idea that there are more
postganglionic than preganglionic fibers. Shares credit with Bernard for discovery of tonic
activity of the sympathetic nerves.
JB Winslow Renamed “intercostalis” “nervi sympathici maximi” as he proposed that the nerves carried (4, 264)
“sympathies” to coordinate various visceral functions; provided extensive description of
three sympathetic nerves: “small sympathetic nerve” (facial); “middle sympathetic nerve”
(vagus); and “large sympathetic nerve” (sympathetic ganglionic chain). Suggested
sympathetic fibers may be of spinal origin; differentiated white and gray rami. Called the
ganglia “little brains” and used the term “sympathetic system.”
1800s
MFX Bichat Coined the terms “La vie organique” for control of visceral function (autonomic) and “La vie (208)
animale” for control of somatic function (somatic); first use of the term “sympathetic
nervous system.”
C Bernard Coined the phrase “milieu interior”; discovered the “vasomotor” function of sympathetic (4, 24-27, 122, 154)
nerves when section of the cervical sympathetic nerve caused vasodilation in the head
and neck stimulation caused vasoconstriction; determined a supraspinal origin of activity
in sympathetic nerves. Bernard also contributed to cholinergic neurotransmission; he
stated that “curare must act on terminal plates of motor nerves” and that “curare does no
more than interrupt something motor which puts the nerve and the muscle into electrical
relationship … required … for the movement.”
O Schmiedeberg and Reported that muscarine and vagal stimulation produced identical cardiac effects and that (154)
R Koppe both were antagonized by atropine (1869).
KG Lange Autonomic responses occur during reflexively during behavior (1885); cardiovascular (225)
adjustments account for sensory experience associated with emotions (e.g., flushing
during embarrassment; increased blood pressure and heart rate during anger).
G Oliver and E Schäfer Found that adrenal medulla released a substance that increases blood pressure (1895). (41, 223)
WH Gaskell Identified white rami as being sympathetic fibers emanating from spinal cord; identified (4, 106, 107)
what is today known as the IML cell column as the origin of sympathetic nerves; preferred
using the term “involuntary nervous system” since this division of the nervous system
functions independently of consciousness.
JN Langley Coined the terms “autonomic nervous system,” “preganglionic neuron,” and “postganglionic (41, 118, 163-167)
neuron”; envisioned the sympathetic and parasympathetic nervous systems to function as
physiological antagonists; found that extracts of the adrenal medulla elicited responses
that were similar to those induced by sympathetic nerve stimulation; noted that curare
blocks autonomic ganglia, similar to its ability to paralyze skeletal muscle; introduced the
concept of receptors for actions of chemicals on effector organs (1905).

(continued)

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Table 2 (Continued)

Individual(s) Discovery References

JJ Abel and J Takamine Working independently, they isolated adrenaline (epinephrine) from the adrenal gland (1, 2, 41, 183, 223,
and identified it as the blood pressure elevating constituent of the adrenal gland. 244, 245)
This was the first hormone to be isolated in a pure state. Takamine received a patent
for the compound; it was marketed as “Adrenalin” by Parke, Davis, & Company,
with whom Takamine had established a working relationship. To avoid trademark
infringement, the United States chose to use the term epinephrine when referring to
the natural chemical released by the adrenal medulla.
1900-1950
R Hunt Noted that adrenal medullary extracts caused a fall in blood pressure after adrenaline (216)
had been removed from the extracts, an effect was initially attributed to choline
(1900); noted that acetylcholine (ACh) was 100,000 times more potent than choline
but assumed it was a poison (1906).
TR Elliott Often credited with first suggesting that neurotransmission is chemically mediated after (85, 223, 251)
noting a similarity between responses elicited by adrenal medullary extract and
sympathetic nerve stimulation in many visceral organs; proposed that sympathetic
fibers release adrenalin; noted that the action of adrenalin was enhanced after
cutting sympathetic innervation to an organ (later called “denervation
supersensitivity”).
WE Dixon and P Hamill Noted a similarity between the actions of muscarine and electrical stimulation of the (73, 257)
vagus nerve on the heart; suggested that excitation of the nerve releases a
muscarine-like substance that acts on some constituent of the end organ to induce a
response.
HH Dale Studied the actions of ergot fungus extracts, including acetylcholine (ACh) on various (65, 66, 68, 153,
organs; described cardiovascular effects (reduced heart rate and blood pressure) of 154, 223, 251)
ACh, an effect similar to parasympathetic stimulation; transient nature of ACh’s
action attributed to its rapid metabolism by an esterase. He noted two types of
responses to Ach, which he referred to as muscarinic and nicotinic since they
mimicked the effects of injecting muscarine (active chemical of the poisonous
mushroom Amanita muscaria) and nicotine, respectively. Dale also coined the terms
“parasympathomimetic” and “sympathomimetic” to describe the actions of
acetylcholine and adrenalin and other chemicals that mimicked the effects of
stimulation of parasympathetic and sympathetic postganglionic nerves, respectively.
O Loewi First decisive physiological evidence that a chemical (vagusstoff) is released by vagus (172, 266)
nerve to reduce heart rate, an effect that is abolished by atropine; stimulation of
vagosympathetic nerve after atropine increased heart rate, showing sympathetic
fibers also released a chemical (acceleransstoff). Loewi also determined that
physostigmine acted by blocking acetylcholinesterase activity. In 1936, Dale and
Loewi were the recipients of the Nobel Prize in Physiology or Medicine for their joint
efforts to explain chemical neurotransmission.
WB Cannon Coined the term homeostasis; sympathetic nervous system prepares animals for fight or (52, 53, 118, 223)
flight whereas parasympathetic nervous system is involved in energy conservation;
proposed that sympathin (a hypothetical chemical released by sympathetic nerves)
combined with excitatory or inhibitory substances at postsynaptic sites to form
sympathin E (excitatory) or sympathin I (inhibitory); described the principle of
denervation supersensitivity.
U von Euler Correctly identified that NE and not epinephrine was the chemical released by (152, 223, 230)
sympathetic fibers; NE was produced and stored in synaptic vesicles in nerve
terminals
ED Adrian, DW Bronk, and First recordings of the spontaneous activity of a postganglionic sympathetic nerve (5)
G Phillips (cardiac nerve activity, anesthetized cat)
O Krayer and W Feldberg Discovered that ACh is released from the vagus nerve of mammals (91)
GH Acheson and G Moe Determined that tetraethylammonium (TEA) could block ganglionic transmission to (3, 250)
account for its ability to reduce blood pressure.
WDM Paton and EJ Zaimes Hexamethonium was found to be a potent ganglionic blocker with a much longer (76, 205, 206, 250)
duration of action than TEA. Paton speculated that this drug “offers possibilities of
clinical usefulness in such fields as hypertension and vascular disease.” This led to
the use of ganglionic blocking agents as the first pharmacological treatment for
hypertension.

(continued)

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Table 2 (Continued)

Individual(s) Discovery References

1950-2000
WF Riker and WC Wescoe First evidence for the existence of muscarinic receptors in the periphery. (219)
KE Hagbarth and ÁB Vallbo First recordings of sympathetic nerve activity (muscle sympathetic nerve activity) in a (126)
conscious human subject.
Julius Axelrod Discovered that NE was recaptured by the nerve terminals from which it was released (14)
(1957) and discovered the enzyme catechol-O-methyltransferase which is involved in the
inactivation of catecholamines (1958). He shared the Nobel Prize in Physiology or
Medicine in 1970 with Bernard Katz and Ulf von Euler for their combined efforts on
explaining the release, reuptake, and storage of neurotransmitters from synaptic vesicles.
AM Lands Identified subtypes of β-adrenoceptors; β1 -adrenoceptors (equally sensitive to NE and (45, 162)
epinephrine) mediate tachycardia and β2 -adrenoceptors (more sensitive to epinephrine
than NE) are responsible for relaxation of the vascular, uterine, and airway smooth
muscle.
JM Petras and JF Cummings Publication of a comprehensive description of cytoarchitecture of preganglionic sympathetic (207)
neurons that remains.
Berthelsen and Pettinger Designation of α1 - and α2 -adrenoceptors based on a functional subdivision. (28, 45)
Amendt et al. The first group to report the results of using retrograde tracing technology to identify the (8)
location of brainstem neurons that project directly to the IML.
F Murad, RF Furchgott, and They shared the Nobel Prize in Physiology or Medicine in 1998 for their independent work (100, 101, 138,
LJ Ignarro leading to the discovery that ACh causes release of nitric oxide (NO) to promote a 139, 155)
vasodepressor response. Murad showed that nitrovasodilators such as nitroglycerin
function via the release of NO (1977); Furchgott found that ACh interacts with muscarinic
receptors on endothelial cells of isolated aortic strips to stimulate the release of a relaxing
factor (1980); Furchgott and Ignarro independently proposed that the endothelium-derived
relaxing factor was NO (1988).

of sympathetic fibers, including determining that the white condition for free and independent life…All the vital mech-
rami communicantes (white communicating branch) is com- anisms, however varied they might be, always have one pur-
prised of sympathetic fibers that arise from the spinal cord pose, that of maintaining the integrity of the conditions of life
(preganglionic fibers) and correctly postulating that a column within the internal environment.” This view of the importance
of cells in the lateral horn of the spinal cord [now known of the constancy of the internal environment for survival was
as the intermediolateral (IML) cell column] is the origin of a revolutionary idea at the time but is now a fundamental tenet
these sympathetic fibers. He also introduced the term prever- of the discipline of physiology in general and of the ANS in
tebral ganglia for sympathetic ganglia located close to the particular.
abdominal and pelvic visceral organs. Cannon is credited as the individual who triggered the
From a physiological standpoint, two individuals that widespread recognition of the importance of Bernard’s the-
merit a focal point on the autonomic neuroscience “family” ory for survival and the fact that adrenaline (epinephrine)
tree are Claude Bernard (1813-1878) and Walter Bradford has a key role in maintaining the constancy of the internal
Cannon (1871-1945). Bernard, a French physiologist in the environment (see review by Goldstein (118). Cannon was an
mid-19th century, is known as the founder of experimental American physiologist who became Professor and Chair of
medicine and modern physiology. He made many significant the Department of Physiology at Harvard Medical School
discoveries about autonomic effector targets including the and the sixth President of the American Physiological Soci-
importance of the pancreas in digestion, the glycemic func- ety. Cannon built on Bernard’s concept of the constancy of the
tion of the liver, a link between blood flow and temperature internal environment when he coined the term homeostasis to
regulation, and the influence of the vagus nerve on heart rate explain how the composition of bodily fluids, body tempera-
(24, 26, 27). But he is perhaps most famously recognized as ture, blood pressure, and other major physiological processes
the individual that coined the phrase milieu interior (trans- can remain relatively constant despite fluctuations and stimuli
lated as “interior environment”). According to Bernard (27), imposed by the external environment (51). In 1996, Schutz
“… the tissues are in fact withdrawn from direct external influ- (228) described homeostasis as follows: “How can we eat
ences and are protected by a veritable internal environment what we want, drink what we want, live where we want, do
which is constituted, in particular, by the fluids circulating in what we want, vary our metabolic rates over a fivefold range,
the body…The constancy of the internal environment is the and stay the same within very narrow limits? And if we stray

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much beyond these limits, we die!” The term homeostasis from the ergot fungus to determine the basis for this oxyto-
has become synonymous with the word physiology. Since cic action. The extracts included ergotoxine and ergotamine
the ANS is responsible for homeostasis, the ANS must be which Dale showed were able to block the stimulatory effects
considered a major foothold for physiology. of adrenaline and sympathetic nerve stimulation on blood
Cannon articulated what he considered to be the key differ- pressure. George Barger, a chemist at Wellcome Laboratories,
ences in the functions of the sympathetic and parasympathetic extracted various chemicals from the ergot fungus including
divisions of the ANS (49, 50). He built on concepts initially histamine, acetylcholine (ACh), tyramine, and several amines
conceived by Langley (166) regarding functional implica- that mimicked the actions of adrenaline. At the time no one
tions of differences in their anatomical organization. Cannon had envisioned that any of these extracts would be found natu-
(50) proposed that the widespread distribution of sympathetic rally in the body. In 1910, Dale noted responses that mimicked
postganglionic fibers together with the fact that a single pre- parasympathetic activation, including a profound fall in heart
ganglionic fiber connects with many postganglionic fibers rate, increased salivation, and contraction of the esophagus,
allow for a diffuse activation of sympathetic nerves and thus stomach, intestines, and bladder upon exposure to ACh (65).
mass activation of its effector targets. In contrast, he regarded He also noted the rapid degradation of these actions of ACh
the discrete distribution of parasympathetic fibers as the basis when it was administered into the blood stream; he even sug-
for specific and separate activation of its target organs. gested that this was due to an enzyme which today we know
Cannon (49, 50) was also instrumental in articulating the to be acetylcholinesterase. Having no indication that ACh was
link between the ANS, especially the sympathetic nervous found naturally in the body (in contrast to adrenaline that was
system, and emotions. Cannon (49) wrote: “It appears that found in the adrenal medulla), Dale was not tempted to sug-
any high degree of excitement in the CNS, whether felt as gest that ACh was released by parasympathetic fibers. Dale
anger, terror, pain, anxiety, joy, grief or deep disgust, is likely also did experiments using norepinephrine (NE) and found
to break over the threshold of the sympathetic division and that it mimicked the actions of adrenaline and sympathetic
disturb the quiet of all the organs which that division inner- stimulation. But again, not realizing that it was found natu-
vates … strong emotions can thus be expressed in the diffused rally in the body, he did not move to the conclusion that it was
activities of a single division of the autonomic—the division released by a sympathetic nerve (68).
which accelerates the heart, inhibits the movements of the The definitive experiments showing that ACh and NE
stomach and intestines, contracts the blood vessels, erects the were released by autonomic nerves awaited the efforts of
hairs, liberates sugar, and discharges adrenalin.” This is the Dale’s friend, Otto Loewi. By the time Loewi began his work
basis of the description of the sympathetic nervous system as on chemical neurotransmission, it had been established that
mediating “fight or flight” response. electrical stimulation of the vagus nerve reduced the rate
From a pharmacological viewpoint Sir Henry Hallett Dale of contraction of the heart, but the mechanism responsible
(1875-1968) and Otto Loewi (1873-1961) are key members for this bradycardia was unknown. In 1921, Loewi provided
of the autonomic neuroscience “family” tree. Dale, an English the first decisive physiological evidence that a chemical is
pharmacologist and physiologist, and Loewi, a German phar- released by the vagus nerve onto the heart to lead to a reduc-
macologist shared the 1936 Nobel Prize in Physiology or tion in the heart rate. Legend has it that the experimental
Medicine for their work leading to the discovery of chem- design came to him in a dream on Easter Sunday night of that
ical transmission of nerve impulses. Historical reviews by year (152, 216, 251, 266). He awoke from the dream, scrib-
Valenstein (251), Rubin (223), and Karczmar (154) provide bled some notes which were indecipherable the next morning.
excellent accounts of the fundamental work by several lab- The following night, the dream recurred so he went directly
oratories over many years that contributed to resolving the to his laboratory at 3:00 AM to conduct a rather straightfor-
controversy over whether nerves communicated with each ward experiment on a frog heart. He isolated the hearts from
other via a chemical or an electrical signal and the critical two frogs, one with and one without its autonomic inner-
role played by the ANS in that debate. vation. The two hearts were attached to cannulae that were
Dale was a student of Gaskell and Langley at Cam- filled with a saline solution. As the vagus nerve of the first
bridge before joining the laboratory of Ernest Starling and heart was electrically stimulated, the saline solution from that
William Bayliss at University College London shortly after heart was allowed to flow over the noninnervated heart. When
they discovered secretin (251). That is where he met Loewi exposed to the effluent from the innervated heart, the nonin-
who was spending a brief time in England to receive train- nervated heart became bradycardic as if its vagus nerve had
ing in pharmacology; and so a lifetime friendship began. In been stimulated. Loewi called the chemical released by the
1904, Dale accepted a position at the Wellcome Physiolog- vagus nerve vagusstoff. He and his colleagues later demon-
ical Research Laboratories in London where he took on the strated that vagusstoff was actually ACh which Dale had pre-
challenge of understanding the basis of the actions of ergot viously demonstrated to be capable of reducing heart rate
fungus which had long been used in folk medicine and was when placed on the heart. Loewi also showed that atropine
under consideration for being marketed for use in the field prevented the effects of vagal nerve stimulation but, impor-
of obstetrics since it caused uterine contractions. Dale began tantly, it did not prevent the release of vagusstoff. Vagusstoff
to test the biological actions of several compounds extracted was inactivated when it was incubated with ground-up heart

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Overview of the ANS Comprehensive Physiology

muscle; this is now known to be due to the powerful actions organs (143,171,173). Some autonomic effector organs (e.g.,
of acetylcholinesterase to enzymatically degrade ACh. Loewi heart, bronchi, stomach, and urinary bladder) are innervated
later went on to show that when the sympathetic nerve of one by both the sympathetic and parasympathetic nervous sys-
heart was electrically stimulated and its effluent was trans- tems; and the two divisions function as physiological antag-
ferred to a noninnervated heart, the rate of contraction of the onists. In other cases (e.g., iris muscles in the eye and sex-
recipient heart also increased as if its sympathetic innervation ual organs) the two divisions of the ANS function syner-
had been activated. These results proved that autonomic nerve gistically to control a function. Other organs are innervated
terminals release chemicals that mediate the changes in car- by only the sympathetic nervous system (e.g., blood ves-
diac function that result from activation of its nerve supply. sels, brown adipose tissue, and pineal gland) or by only
Obviously, over time it was proven that this is the dominant the parasympathetic nervous system (e.g., ciliary muscle and
mode of neurotransmission in both the peripheral and central nasopharyngeal glands). This variation in innervation pat-
divisions of the nervous system. terns is the topic of some interesting discussions of regulatory
control. Examples of these different patterns of control of
autonomic target organs are described below under Physio-
Major Functions of the Autonomic logical Actions of Sympathetic and Parasympathetic Outflow:
Nervous System Antagonistic, Synergistic, and Independent Control of Target
Organs.
The ANS influences the function of nearly every tissue in The sympathetic nervous system is often defined as being
the body as it provides the innervation to smooth muscle the “fight or flight” division of the ANS. This has a basis in
(e.g., blood vessels, hair follicles, gastrointestinal tract, uri- the work of Cannon (49, 50) in which he described a mass
nary bladder, and sphincter muscles in gastrointestinal and activation of the sympathetic nervous system during various
urinary tracts), cardiac muscle and pacemaker cells, exocrine emotions (fear, rage, and pain). Somehow this led to the over
(e.g., sweat, salivary, respiratory tract, digestive tract, and simplification that the major role of sympathetic nervous sys-
pancreatic) and endocrine (e.g., pineal; islet cells of the pan- tem was to allow individuals to respond to danger, threats, and
creas) glands, white and brown adipose tissue, liver cells, and stress. But, to the contrary, the sympathetic nervous system
lymphatic tissue (143). also controls its effector organs under nonemergency situ-
The list of physiological processes regulated by the ANS ations. As demonstrated by recording from many different
is very long and includes: airway resistance, blood flow, blood sympathetic nerves (both whole nerve and individual fiber
pressure, body temperature, digestion, energy balance, excre- recordings), there is ongoing sympathetic nerve activity under
tion of wastes, fluid volume, glucose homeostasis, heart rate, resting conditions in conscious animals and human subjects
immune system, inflammatory processes, glandular secre- (5, 16, 20, 59, 124, 126, 146). Indeed, tone in the arterioles is
tions, papillary diameter, salt and water balance, and sex- maintained by this basal level of sympathetic nerve activity
ual function (143, 171, 173). Some of these are discussed as evidenced by a fall in arterial pressure after sympathetic
in detail in other articles within Comprehensive Physiology ganglionic blockade (159,250,267). Also, ongoing activity in
(30, 37, 69, 149, 158, 191, 194, 247). The ANS carries out its sympathetic nerves to the detrusor muscle causes relaxation
functions without requiring a conscious effort, so it is some- of the urinary bladder while it is being distended as it fills
times referred to as the involuntary nervous system. The ulti- with urine (112). Loss of sympathetic activity also prevents
mate responsibility of the ANS is to ensure that the physio- ejaculation in males (186).
logical integrity of cells, tissues, and organs throughout the Another misconception arising from the mass sympathetic
entire body is maintained (homeostasis) despite perturbations activation during intense emotions is that all elements of the
exerted by both the external and internal environments. sympathetic nervous system typically work in unison, that
This long list of physiological processes regulated by the is, an “all-or-none” response. In contrast, there is substantial
ANS contrasts with the list of functions regulated by the anatomical and physiological evidence for differential regu-
somatomotor nervous system (127, 151, 211, 233, 239). Both lation of sympathetic outflow to functionally specific targets
α-motor neurons and γ-motor neurons have a singular action: (140, 193).
contraction of the extrafusal (α-motor neurons) or intrafusal The parasympathetic nervous system is often referred to
(γ-motor neurons) fibers within skeletal muscle. They are as the “rest and digest” system in recognition of its role in con-
often coactivated and thus work in synchrony to mediate serving energy, promoting digestion, and ridding the body of
skeletal muscle contraction with the goal of allowing for gross wastes. But just as fight and flight was an inaccurate definition
and fine motor control to maintain posture and balance and to of the overall role of the sympathetic nervous system, rest and
permit locomotion, eye movements, vocalization, and swal- digest does not encompass fully the role of the parasympa-
lowing. thetic nervous system. The effects of parasympathetic nerve
The two anatomically and functionally distinct divi- activity on the eye through contraction of the ciliary muscle
sions of the ANS (the sympathetic and parasympathetic ner- (accommodation for near vision), lacrimal gland (tear produc-
vous systems) can function antagonistically, synergistically, tion), and sphincter muscle (papillary constriction) as well as
or independently to control their many autonomic effector parasympathetic control of sexual organs (erection) are some

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examples of functions of this division of the ANS that are not dogs (46). Other preganglionic neurons have been identified
captured by the terms rest and digest. medial to the IML in a region of the gray matter called the
intercalated nucleus or scattered within the white matter of
the lateral funiculus, immediately adjacent to the IML in the
more rostral segments of the thoracic spinal cord. Whether
Anatomical Organization of neurons located in these four distinct distributions serve the
Sympathetic Preganglionic and same or different functions remains a topic of research.
Postganglionic Neurons The morphology of cell bodies of sympathetic pregan-
glionic neurons is quite variable, with most having a small
To appreciate how the sympathetic and parasympathetic ner- to medium sized diameter and oval or spindle (fusiform)
vous systems exert their many actions on the body, one shape and a few with a large diameter and a multipolar shape
needs to understand the anatomical organization of the ANS (46, 70, 71, 171, 200, 207). The soma of sympathetic pregan-
(46, 71, 171, 190). Figure 1 shows the overall distribution of glionic neurons are about half the size of α-motor neurons but
sympathetic and parasympathetic nerves in the body. The are larger than many dorsal horn neurons. Preganglionic neu-
cell bodies of the sympathetic preganglionic neurons are rons have extensive dendritic trajectories, ranging from 1.5 to
found within a limited longitudinal extent of the spinal cord 2.5 mm in cats (70). For neurons within the IML, the dendrites
(46,71,171). The cervical, except for the caudal end of the 8th are predominantly aligned planarly in the rostral-caudal axis
cervical segment in some species (47,63), and sacral levels of of the spinal cord. Most synaptic input to sympathetic pregan-
the spinal cord are devoid of sympathetic preganglionic neu- glionic neurons likely occurs within the dendritic tree (46).
rons. Sympathetic preganglionic neurons are confined to the The axon of a sympathetic preganglionic neuron emanates
first thoracic through the first few lumbar spinal segments (L2- some distance from the cell body and is a direct extension
L5, depending on the species). This is why the sympathetic of a first-order (or occasionally a second-order) large den-
nervous system is also called the thoracolumbar division of drite, proceeds ventrally, to traverse along the lateral margin
the ANS. The parasympathetic nervous system is called the of the ventral horn without evidence for axonal branching
craniosacral division of the ANS because of the location of (70, 217). In contrast to the large diameter and rapidly con-
its preganglionic neurons; preganglionic neurons are located ducting α-motor neurons and cranial nerve motor neurons,
in several cranial nerve nuclei (III, VII, IX, and X) in the mid- the axons of most preganglionic neurons are small-diameter,
brain, pons, and medulla and in the IML of the sacral spinal lightly myelinated, and slowly conducting B fibers; the axons
cord (208). of some sympathetic preganglionic neurons are unmyelinated
In contrast to the restricted spinal localization of auto- (46, 64, 87).
nomic neurons, the cell bodies of α- and γ-motor neurons are In 1906, Charles Sherrington (232) referred to the α-motor
distributed throughout the length of the spinal cord, from the neurons as “the final common pathway” because they pro-
cervical to sacral levels. These are the neurons that control vide the direct link between the CNS and skeletal muscles in
the skeletal muscles in the limbs and trunk. There are cor- the limbs and trunk. Like α-motor neurons, sympathetic and
responding groups of motor neurons in most of the twelve parasympathetic preganglionic neurons can also be described
cranial nerve nuclei (with the exception of cranial nerves I, as the final common pathway from the CNS; but rather than
II, and VIII) that innervate skeletal muscles of the head and synapsing directly on the effector organ like α-motor neurons,
neck. these neurons synapse on another neuronal type, the postgan-
glionic neuron, which comprises the autonomic ganglia.
Figure 2 shows some of the possible trajectories of the
Sympathetic preganglionic neurons axons of sympathetic preganglionic neurons as they exit the
Whereas the cell bodies of α- and γ-motor neurons are located spinal cord at the segmental level at which their cell bod-
bilaterally within the ventral horn (lamina IX) of the spinal ies are located. These fibers exit via the ventral root along
cord, the cell bodies of sympathetic preganglionic neurons with axons of α- and γ-motor neurons (70,112,199,199,222).
are distributed in four regions of the spinal gray matter in Shortly after exiting the CNS, they separate from the ventral
a bilateral and symmetrical pattern (46, 71, 171, 207). The root and form the white rami (ramus, branch). This ramus is
majority of the neurons are located in the lateral horn within white because of the lightly myelinated axons of most pregan-
the IML cell column (lamina VII) where they tend to be glionic neurons. From here, the preganglionic axons follow
found in clusters of 20 to 100 neurons to form “nests” that one of four trajectories (112,190,211). One, the axons of some
are separated by 200 to 500 μm in the thoracic region and by preganglionic neurons project ipsilaterally and terminate on
100 to 300 μm in the lumbar region (200). A second grouping the cell bodies of postganglionic sympathetic neurons in the
of sympathetic preganglionic neurons is located within the adjacent sympathetic paravertebral ganglion. Two, the axons
central autonomic nucleus dorsal to the central canal (lamina of some preganglionic neurons travel rostrally or caudally to
X), primarily within the caudal thoracic and upper lumbar terminate on postganglionic neurons located ipsilaterally in a
levels. The number of such neurons vary, depending on the paravertebral ganglion at some distance away from the exit
species with more found in guinea pigs than rats, cats, and point of the preganglionic neuron from the spinal cord. These

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Overview of the ANS Comprehensive Physiology

Ciliary ganglion
Edinger-Westphal nucleus III
Pupillary constrictor
and ciliary muscles

Sphenopalatine ganglion
Lacrimal, oral, and
Geniculate
nasal glands
ganglion
Pupillary dilator Submandibular ganglion
Sup. salivatory nucleus
Inf. salivatory nucleus VII Submaxillary and
Lacrimal and sublingual glands
nasal glands
Dorsal motor nucleus Otic ganglion
IX
Submaxillary and of vagus NTS
Nucleus ambiguus Parotid gland,
sublingual glands X cerebral circulation
Nodose
Parotid gland ganglion

Visceral sensory afferents


Sup.
sympathetic
ganglion
Heart Larynx,
C8 esophagus
T1 Heart
Stellate
Lungs ganglion Respiratory tract,
T2
lungs
T3
Diaphragm
Stomach T4

Greater T5
splanchnic Stomach
Liver nerve T6
Liver
Pancreas T7
Pancreas
T8
Celiac
Spleen ganglion
T9 Spleen
T10 Small
Kidney
T11 intestine

T12

Small intestine L1
Mesenteric Colon
ganglia
L2
Colon
Rectum
Rectum
Kidney
S1
Bladder S2
Bladder
S3 Pelvic
nerves
Sex organs
Sex organs
Inf. hypogastric
plexus
Sympathetic
chain

Sympathetic system Parasympathetic system

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Comprehensive Physiology Overview of the ANS

Dorsal root ganglion


Intermediolateral
Spinal cord (T1-L3)
column
Paravertebral
Sensory
sympathetic chain
afferent
fibers

Sympathetic Paravertebral
preganglionic sympathetic
neurons ganglion

White ramus
Motor fibers communicans
Ventral horn
Sympathetic
postganglionic
neurons Gray ramus
communicans

Sympathetic
ganglion Postganglionic
sympathetic fibers
in mixed spinal nerve

Figure 2 Projections of sympathetic preganglionic neurons to paravertebral or prevertebral ganglia or the adrenal
medulla. The axons of sympathetic preganglionic neurons leave the spinal cord at the segment of origin of their cell
bodies within the IML column. These fibers exit via the ventral root with the axons of α- and γ-motor neurons; sympathetic
preganglionic fibers separate from the ventral root to form the white ramus to then terminate on postganglionic neurons in
the adjacent or distant paravertebral ganglia or in prevertebral ganglia in the he abdominal and pelvic region. Another
possible trajectory is to terminate on chromaffin cells in the adrenal medulla (not shown). Visceral sensory afferents are
intermingled with sympathetic efferent fibers and travel with somatic afferents via the dorsal root to terminate in the spinal
cord dorsal horn. Preganglionic nerves are shown in red, postganglionic nerves are shown in black, visceral sensory
afferents are shown in blue, and somatic afferents are shown in green.

paravertebral ganglia are located adjacent to each thoracic located in ganglia that are some distance away, and the axons
and upper lumbar spinal segment; in addition, there are a few of postganglionic neurons that travel a distance before they
ganglia adjacent to the cervical (superior, middle, and inferior branch out to project toward their effector organ.
cervical ganglia) and sacral spinal segments. The sympathetic A third possible trajectory of axons of sympathetic pre-
chain is a bilateral structure located adjacent to the vertebral ganglionic neurons is to pass through paravertebral ganglia
column (Fig. 1). It is comprised of the paravertebral ganglia, to terminate on postganglionic neurons located in prever-
the axons of the preganglionic neurons that travel rostrally tebral (also called collateral) ganglia that are located near
or caudally to terminate on postganglionic neurons that are the abdominal and pelvic visceral targets they innervate.


Figure 1 Schematic of the ANS showing the distribution of sympathetic (left) and parasympathetic nerves (right) in vertebrates. Sympathetic
preganglionic neurons are primarily located in the first thoracic through the first few lumbar spinal segments, which explains why it is also called
the thoracolumbar division of the ANS. In some species, there are also preganglionic neurons located in the caudal portion of the eighth cervical
segment (shown as a dashed line). Paravertebral sympathetic ganglia (located adjacent to the vertebral column) are “connected” via the axons of
the preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance, forming the sympathetic
chain. Parasympathetic preganglionic neurons are located in several cranial nerve nuclei (III, VII, IX, and X) and in the sacral spinal cord, which
explains why it is also called the craniosacral division of the ANS. Postganglionic parasympathetic neurons are located close to or within the target
organ. Visceral sensory afferents that are intermingled with parasympathetic efferent fibers in the thoracic, abdominal, and pelvic cavities are also
shown. These afferent fibers synapse in the nucleus of the tractus solitarius (NTS) in the brainstem. Cranial nerve nuclei I, VII, and IX and sacral
parasympathetic nerves also contain visceral sensory fibers (not shown). Visceral sensory afferents are also intermingled with sympathetic efferent
fibers as shown in Figure 2. Cholinergic neurons are shown in black; noradrenergic neurons are shown in red; visceral sensory fibers are shown
in gray.

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Table 3 Topographical Organization of Sympathetic Preganglionic Neurons

Spinal segments Ganglion Effector targets

T1-T2 Superior cervical Pupillary muscles of the eye; submandibular, sublingual, and parotid
glands
T1-T5 Superior and middle cervical Sweat glands and the vasculature of the head and neck; vasculature of
the brain; choroid plexus; carotid body
T1-T7 Stellate and other upper thoracic Heart
T2-T7 Stellate and other upper thoracic Trachea; bronchii; lungs
T3-T6 Stellate and other upper thoracic Brown adipose tissue, sweat glands, erector pili muscles, and
vasculature of upper extremities
T5-T6 Stellate and other upper thoracic Esophagus
T4-T12 Adrenal gland Chromaffin cells of the adrenal medulla
T6-T11 Celiac Smooth muscle and glands of the stomach; liver; gallbladder; pancreas
T8-T12 Aorticorenal Tubules of the renal cortex; renal blood vessels; proximal convoluted
tubules; glomeruli; pelvic wall
T9-T10 Celiac, superior, and inferior mesenteric Small intestine; ascending limb of large intestine
T10-L2 Lumbar and upper sacral Sweat glands, erector pili muscles, and vasculature of lower extremities
T11-L1 Celiac, superior, and inferior mesenteric Transverse large intestine
T11-L2 Inferior mesenteric, hypogastric, and pelvic Descending large intestine, colon, and rectum
T11-L3 Hypogastric and pelvic Urinary bladder; male reproductive system (epididymis, vas deferens,
seminal vesicles, and prostate glands); female reproductive system
(vagina and uterus)

These include the celiac, aorticorenal, superior mesenteric, within the spinal cord (46, 71, 143, 243). Specifically, neu-
and inferior mesenteric ganglia. In contrast to the paraver- rons in upper thoracic spinal cord segments project to more
tebral sympathetic chain which is a bilateral structure, these rostrally located sympathetic ganglia and the neurons in the
prevertebral ganglia are not found in pairs. These ganglia lower thoracic and upper lumbar spinal segments innervate
receive input from preganglionic neurons whose cell bodies postganglionic neurons located in the most caudal ganglia.
are located on the same (80%) or opposite (20%) side of the Table 3 shows the location of preganglionic neurons labeled
spinal cord (17-19,144,145). A fourth possible route taken by following injection of a retrograde tracer into several discrete
sympathetic preganglionic axons is to terminate directly on ganglia in rats (243) and the distribution of postganglionic
an effector organ, the catecholamine-producing chromaffin fibers from these ganglia (12, 74, 143, 160, 198). Some of the
cells in the medullary portion of the adrenal gland. Not only postganglionic neurons that emerge from the middle cervical
do adrenal medullary cells function similarly to sympathetic and stellate ganglia join the upper cervical (C1-C4) ventral
postganglionic neurons, but they have embryologic similari- roots to travel to sweat glands, erector pili muscles (also called
ties as well, with both being derived from neural crest cells arrector pili muscle or pilomotor muscle), and the vasculature
(143,190). So a chromaffin cell of the adrenal medulla can be of neck and face. Likewise, some of the postganglionic neu-
defined as a sympathetic ganglion cell that has lost its axons rons that emerge from the stellate and upper thoracic chain
and secretes its transmitter directly into the blood stream. But, ganglia join the ventral roots of the lower cervical segments
in addition to releasing NE like a postganglionic sympathetic (C6-C8) to innervate the sweat glands, erector pili muscles,
nerve, the adrenal medulla also releases epinephrine, the N- and vasculature of the forelimb and the thoracic wall. Simi-
methyl derivative of NE, directly into the systemic circulation. larly, postganglionic fibers from the lower thoracic and upper
The axons of many sympathetic preganglionic neurons lumbar chain ganglia innervate the sweat glands, erector pili
are relatively short (compared to those of α-motor neurons) muscles, and vasculature of the hindlimb. As one might pre-
since they synapse on postganglionic neurons located within dict based on the information in Table 3, when recording
the sympathetic chain located bilaterally adjacent to the spinal from an individual sympathetic preganglionic neuron, it is
cord. In contrast, the axons of the sympathetic postganglionic often difficult to predict its effector target because function-
neurons are much longer than the sympathetic preganglionic ally distinct neurons are intermixed within the thoracolumbar
axons since they continue on to the effector organ. IML cell column.
As is the case for the distribution of α-motor neurons, sym- One similar feature of autonomic preganglionic neurons
pathetic preganglionic neurons are topographically organized and α-motor neurons is that ACh is released at their nerve

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Comprehensive Physiology Overview of the ANS

terminals. Indeed, ACh is the neurotransmitter released by muscle cell and then makes similar contacts further down the
all neurons whose axons directly exit the CNS. This includes target is called a synapse en passant.
cranial nerve III, V, VII, IX, X, XI, XII motor neurons, spinal This pattern of synapse between a sympathetic postgan-
α-motor neurons, spinal γ-motor neurons, spinal sympathetic glionic nerve terminal and its effector target is in sharp con-
preganglionic neurons, and spinal and cranial nerve III, VII, trast to the pattern for α-motor neurons (127, 151, 211, 233,
IX, and X preganglionic parasympathetic neurons. As will 239). As the axon of the α-motor neuron approaches its ter-
be described in more detail below under Cholinergic Neuro- mination, it loses its myelin sheath and divides into several
transmission: Acetylcholine Synthesis, Storage, Release, and terminal boutons. These nerve endings are embedded into
Degradation, the ACh released by all of the nerves that exit folds or grooves on the thickened surface of the skeletal mus-
the CNS acts on ligand-gated ion channels called nicotinic cle fiber, a region called the motor end plate (234). A synaptic
receptors, but the specific type of nicotinic receptor in auto- cleft separates the nerve terminal from the skeletal muscle
nomic ganglia (NN ) is different from that in the neuromuscular membrane and is comparable to that seen at neuron-to-neuron
junction (NM ). synapse. The combination of nerve terminal, synaptic cleft,
and motor end plate is known as the neuromuscular junction
(34, 54, 127, 151, 211, 239).

Sympathetic postganglionic neurons


Functionally distinct groups of sympathetic postganglionic
neurons intermingle in the paravertebral and prevertebral gan- Anatomical Organization of
glia. The axons of some postganglionic neurons leave the par- Parasympathetic Preganglionic and
avertebral ganglia and reenter the spinal nerves via the gray Postganglionic Neurons
rami and project to and terminate on autonomic effectors in
the areas supplied by these spinal nerves (Fig. 2). This ramus Like the axons of sympathetic preganglionic neurons, the
appears gray due to the lack of myelin which is characteristic axons of preganglionic parasympathetic neurons are lightly
of the axons of most if not all sympathetic postganglionic myelinated or unmyelinated and have slow conduction veloc-
neurons. These sympathetic postganglionic axons that travel ities. The axons of many parasympathetic preganglionic neu-
via the spinal nerve terminate mainly on smooth muscle (e.g., rons are relatively long (not unlike those of α-motor neurons)
blood vessels and hair follicles) and on sweat glands in the since they synapse on postganglionic neurons located near or
forelimbs and hindlimbs. Other sympathetic postganglionic within the wall of the target organ. In such cases, the axons
fibers leave the paravertebral chain ganglia to enter the tho- of parasympathetic postganglionic neurons are very short.
racic cavity and project to and terminate on visceral organs The organization of parasympathetic neurons is consid-
such as the heart and bronchi. The axons of sympathetic post- erably different than that of sympathetic neurons. In contrast
ganglionic neurons within prevertebral ganglia terminate on to the intermingling of functionally diverse pools of sym-
visceral targets such as the gastrointestinal tract, urinary blad- pathetic preganglionic neurons described above, parasym-
der, kidney, and pelvic organs. pathetic preganglionic neurons are located in cranial nerve
At least in the case of sympathetic postganglionic neurons nuclei with a defined anatomical and functional target. Thus it
projecting to smooth muscles, the axons branch extensively is fairly straightforward to predict the end organ that a pregan-
and come in close contact with the membrane of smooth glionic parasympathetic neuron will influence. And because
muscle cells. Most of these nerve fibers contain dense-core parasympathetic postganglionic neurons are mostly located
vesicles which is characteristic of NE-containing vesicles within the structure it innervates, it is easy to predict their
(143). Others contain clear vesicles, characteristic of ACh- function as well.
containing vesicles. There are no recognizable postsynaptic The Edinger-Westphal nucleus contains the cell bodies
specializations at the junction of a sympathetic postganglionic of some of the neurons that form the oculomotor nerve (cra-
neuron and a smooth muscle fiber. The nerve fibers traverse nial nerve III) within the midbrain. This nucleus has clas-
along the membranes of the smooth muscle and sometimes sically been considered to be the location of preganglionic
groove their surfaces. The multiple branches of these sym- cholinergic parasympathetic neurons that project to the cil-
pathetic postganglionic fibers are beaded with enlargements iary ganglion and provide parasympathetic control of the eye
called varicosities that contain synaptic vesicles. In neurons (135, 136, 173). This is indeed the case in the monkey and
with NE-containing vesicles, the varicosities are ∼1-μm wide in birds, but in other species (e.g., mouse, rat, ferret, cat,
and ∼5 μm apart; and an individual sympathetic neuron can and human) the Edinger-Westphal nucleus does not contain
have as many as 20,000 varicosities. The neurotransmitter cholinergic neurons. In the mouse, rat, rabbit, and cat, pre-
is apparently released from the vesicles at each of the many ganglionic parasympathetic neurons to the ciliary ganglion
varicosities along the axon branches, allowing a single sympa- are scattered outside of the Edinger-Westphal nucleus and in
thetic postganglionic neuron to innervate many effector cells the perioculomotor region, ventral to the oculomotor nucleus
within the smooth muscle. This type of contact in which a (135). In humans, preganglionic parasympathetic neurons to
neuron forms a synapse with another neuron or a smooth the ciliary ganglion are found dorsal to the oculomotor nucleus

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Overview of the ANS Comprehensive Physiology

(135, 136). The ciliary ganglion contains the cell bodies of atrioventricular nodes in the heart as well as the soft palate,
postganglionic neurons that form the ciliary nerve that inner- pharynx, larynx, upper airway accessory muscles, and striated
vates the sphincter (constrictor) muscle of the iris to cause muscles within the esophagus and upper esophageal sphinc-
pupillary constriction (miosis) and the circumferential mus- ter. The nucleus ambiguus does not supply subdiaphragmatic
cles of the ciliary body (ciliary muscle) to control accommo- organs; preganglionic parasympathetic neurons controlling
dation for near vision. As pointed out by Gibbins (112), the those structures are located in the dorsal motor nucleus of the
parasympathetic innervation to the ciliary muscle may be the vagus. The preganglionic axons emanating from the dorsal
single example in which the ANS provides voluntary rather motor vagal nucleus are primarily unmyelinated and innervate
than involuntary control of a target organ. An individual can postganglionic neurons in the gastrointestinal tract from the
voluntarily chose where within the visual field to focus. For a stomach to the transverse colon as well as the liver and pan-
recent comprehensive review of the autonomic control of the creas. Postganglionic parasympathetic neurons within tho-
eye, readers should refer to McDougal and Gamlin (191). racic visceral organs, including the heart, trachea, bronchii,
Parasympathetic preganglionic neurons are scattered in and lungs, also receive some input from the dorsal motor
the pontine tegmentum in a region called the superior sali- nucleus of the vagus although their dominant input is from
vatory or lacrimal nucleus in many species including cats, vagal preganglionic neurons within the nucleus ambiguus in
hamsters, rabbits, rats, and monkeys (263). The precise loca- most species.
tion of the superior salivatory nucleus in humans has not been In addition to the cranial division of the parasympathetic
identified. Preganglionic axons travel with non-autonomic nervous system, there is also a component of the parasym-
fibers as part of the intermediate nerve, a branch of the pathetic outflow that originates in the sacral spinal cord.
facial nerve (cranial nerve VII), to reach the geniculate gan- This component forms the pelvic nerve which supplies the
glion. From here, the intermediate nerve divides into two pelvic viscera, including the detrusor and urethral sphinc-
branches. One branch is called the greater petrosal nerve ter smooth muscles, colon, vaginal and prostate glands, and
which contains the parasympathetic fibers that project to the blood vessels to the penis (112, 208, 211, 216). Another name
sphenopalatine (or pterygopalatine) ganglion. This ganglion for this sacral parasympathetic nerve bundle is the nervi eri-
contains the cell bodies of parasympathetic postganglionic gentes since genital erection occurs during activation of this
neurons that innervate the lacrimal glands and nasal, pala- nerve. The cell bodies of the pelvic nerve are located pri-
tine, and pharyngeal mucosal glands. The cerebral circula- marily in laminae V-VII (including the IML) of the second
tion also receives innervation from parasympathetic postgan- through fourth sacral spinal cord segments. The parasym-
glionic fibers exiting from the sphenopalatine ganglia (117). pathetic pelvic nerve fibers join the postganglionic sympa-
The other branch of the intermediate nerve is called the chorda thetic fibers within the hypogastric nerve to form the infe-
tympani or lingual nerve which includes the parasympathetic rior hypogastric plexus which projects to the target organs.
preganglionic fibers that project to the submandibular gan- The pelvic nerve terminates on ganglia in the pelvic plexus
glion (77, 133, 263). This ganglion contains the cell bodies (including the hypogastric ganglia and paracervical ganglia
of postganglionic neurons that innervate the submandibular in females) that are scattered near the bladder, rectum, and
(formerly called submaxillary) and sublingual glands. genitalia.
The axons of parasympathetic preganglionic neurons from
the medullary inferior salivatory nucleus travel with non-
autonomic fibers within the glossopharyngeal nerve (cranial Convergence and Divergence within
nerve IX) (77, 133, 263). Once the nerve reaches the inferior Autonomic Ganglia
ganglion, a small branch of the IXth cranial nerve (Jacobsen’s
nerve) containing the parasympathetic fibers separates from Autonomic ganglia are not simple relay stations; rather, a sig-
the other fibers to join the tympanic nerve to reach the tym- nificant amount of integration of information occurs within
panic plexus. From here the parasympathetic preganglionic these structures due to convergent and divergent connections
fibers form the lesser petrosal nerve which synapses in the made by preganglionic nerve terminals onto the postgan-
otic ganglion. The axons of the postganglionic neurons within glionic neurons (197). As reviewed by Wang and colleagues
this ganglion join a branch of the trigeminal nerve and form (259), the pattern of connections between preganglionic and
the auriculotemporal nerve to innervate the parotid salivary postganglionic neurons within the sympathetic and parasym-
gland; postganglionic fibers leaving the otic ganglion also pathetic divisions of the ANS has been the subject of many
innervate the cerebral circulation (77, 117). anatomical studies dating back to a 1918 study of Billingsley
Vagal preganglionic neurons (within cranial nerve X) are and Ranson (29). Typically the axon of a preganglionic neuron
located in two distinct nuclei: the nucleus ambiguus and dor- diverges to synapse on multiple postganglionic neurons within
sal motor vagal nucleus in the medulla (148, 175). Vagal pre- a ganglia or in different ganglia to influence a pool of neu-
ganglionic neurons are arguably the best-characterized com- rons. This process of divergence is a mechanism by which a
ponent of the parasympathetic nervous system. The nucleus relatively few preganglionic neurons can alter the activity of a
ambiguus contains neurons with lightly myelinated fibers that much larger pool of postganglionic neurons to thus effectively
innervate postganglionic neurons within the sinoatrial and enhance the effector response (143). Likewise, activation of

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a postganglionic neuron is generally dependent on receiving foundation for the overgeneralization that the activation of
input from the convergence of more than one preganglionic parasympathetic preganglionic neurons leads to discrete acti-
neuron. As a result of these connections, information from the vation of its autonomic effector organs, whereas the activation
CNS to these peripheral autonomic ganglia may be amplified of sympathetic preganglionic neurons causes widespread, dif-
or reduced and may be either localized or diversified. fuse activation of its target organs.
The superior cervical ganglion has been the focus of The term “neural unit size” has been used to describe
many studies to quantify the ratio of preganglionic to post- the single preganglionic neuron and all of the postganglionic
ganglionic neurons in sympathetic ganglia (35, 79, 213, 214). neurons it innervates (46, 212, 213). This is comparable to the
What becomes very evident from such studies is that the num- term “motor unit size” to describe the divergence pattern of a
ber of postganglionic neurons far surpasses that of pregan- single α-motor neuron to a group of muscle fibers (127, 151,
glionic neurons. The axon terminals of a single sympathetic 211, 233, 239). The term “motor unit” refers to each α-motor
preganglionic neuron may diverge to synapse on as few as one neuron and the muscle fibers it innervates; and all of the motor
to as many as 100 postganglionic neurons (113, 143). Thus, units within a muscle form a “motor pool.” The motor unit size
a single sympathetic preganglionic neuron potentially could varies based on the function of the muscle group innervated
exert very discrete effects on autonomic function or a more with fine motor control areas having smaller motor units and
diffuse influence. The pattern of divergence varies among dif- bulk movement muscle groups having large motor units. For
ferent ganglia and between different species. Using the above example, in humans the motor unit size ranges from 5 (i.e.,
numbers within the superior cervical ganglion, on the average, one motor neuron contacts 5 muscle fibers) for lateral rectus
an individual preganglionic fiber diverges to innervate ∼100 muscle in the eye to about 2,000 (i.e., one motor neuron
neurons in the superior cervical ganglion in humans, ∼27 contacts 2000 muscle fibers) in the medial gastrocnemius
postganglionic neurons in the rat, and ∼14 postganglionic muscle of the leg (88). To estimate the ANS neural unit size,
neurons in the mouse (79, 213). However, when using elec- one simply multiples the divergence ratio by the degree of
tron microscopy to assess the composition of elements within convergence (46). At least in the case of the superior cervical
the superior cervical ganglion of the rat, Brooks-Fournier and ganglion, the neural unit size increases as the size of the
Coggleshall (35) reported that the ratio of sympathetic pre- animal increases, going from an average of 64 ganglion cells
ganglionic to sympathetic postganglionic neurons was only innervated by a single preganglionic neuron in mice up to 422
1:4. Regardless of the exact number, these anatomical studies ganglion cells in the rabbit (212, 213).
do not inform us as to whether an individual preganglionic
neuron can influence the activity of postganglionic neurons
that serve different functions. For example, it has yet to be Visceral Sensory Fibers
determined whether an individual preganglionic neuron can
activate a postganglionic neuron that innervates the vascu- In 1906 Sherrington (232) introduced the term interorecep-
lature of the head as well as one that innervates the radial tor and interoreception to define transmission of sensory
muscle of the iris. information coming from the internal visceral organs. The
As is the case for divergence, the convergence pattern term was used as a comparison to transmission of sensory
varies considerably among autonomic ganglia, but in general information from the body surface (exteroception) and from
the number is much higher for sympathetic neurons than for deep within somatic tissues (proprioception). Visceral sen-
parasympathetic neurons (112). Purves and Lichtman (212) sory fibers are small, lightly myelinated Aδ or unmyelinated
compared the convergence pattern within the superior cervi- C fibers and relay mechanosensitive and chemosensitive infor-
cal ganglion in several species (mouse, hamster, rat, guinea mation to the CNS which can respond to both physiological
pig, and rabbit). They made intracellular recordings from a and pathophysiological (e.g., ischemia, inflammation) stimuli
large sample of superior cervical ganglion neurons and deter- (62, 69, 94, 123, 125, 136, 137, 143, 147, 225). These visceral
mined the average number of preganglionic fibers that inner- sensory afferents function to provide feedback to the CNS
vated each postganglionic neuron. They noted that the larger concerning the status of the autonomic effector organs within
the body size, the larger the convergence ratio. For example, the head and neck and the thoracic, abdominal, and pelvic
each sympathetic postganglionic neuron in the rabbit superior body cavities and to help maintain homeostasis (143, 225).
cervical ganglion was innervated by an average of 15.5 pre- Afferent fibers from visceral organs and tissues are typ-
ganglionic neurons compared to 4.5 preganglionic neurons in ically intermingled with sympathetic and parasympathetic
the mouse ganglion. (e.g., glossopharyngeal and vagal) nerve fibers in peripheral
Wang et al. (259) used the term ratio index to describe nerve bundles (62, 123). The cell bodies of visceral sensory
the ratio of preganglionic to postganglionic neurons. They fibers are located within spinal dorsal root ganglia and the cra-
noted that historically, the ratio for parasympathetic ganglia nial nodose ganglia; they convey visceral sensory information
was typically reported to be one preganglionic neuron to a to the dorsal horn of the spinal cord and nucleus of the trac-
few postganglionic neurons, and the ratio for sympathetic tus solitarius in the brainstem (see Figs. 1 and 2). Although
ganglia was commonly stated to be one preganglionic neuron these sensory fibers are often referred to as sympathetic or
to many postganglionic neurons. This is assumed to be the parasympathetic afferents, this is perhaps not an appropriate

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term. From a historical perspective, Langley (163-167) was the capacity to synthesize both NE and ACh based on the
very careful to use the terms sympathetic and parasympathetic expression of both tyrosine hydroxylase and choline acetyl-
only when referring to efferent fibers. Janig (143) provided transferase. Under the influence of some conditioning factors,
a rational explanation as to why the terms sympathetic and neurons segregate into those synthesizing only NE or only
parasympathetic afferents can be misleading and why it is ACh.
preferable to use the term visceral afferents when referring to Transmission at the neuromuscular junction is also
sensory fibers relaying information from autonomic effector chemically-mediated (234). The axon terminals of α-motor
organs to the CNS. The terms sympathetic and parasympa- neurons contain round, clear synaptic vesicles containing the
thetic afferents imply that these fibers have functions that neurotransmitter, ACh. ACh is released from the nerve ter-
are unique to a single division of the ANS. Rather, it is not minal and then acts on nicotinic receptors located on the
uncommon for both divisions of the ANS to respond to acti- junctional folds of the motor end plate to initiate the process
vation of visceral sensory receptors that relay information for muscle contraction.
via either the sympathetic nerves or parasympathetic nerves. Autonomic neuroeffector junctions are a logical site for
Also, arterial baroreceptors relay information via “parasym- pharmacologic manipulation of autonomic function. As will
pathetic” cranial nerves even though the receptors are located be described in more detail below, ACh and NE are synthe-
in target organs (vasculature) that are innervated exclusively sized, stored in the nerve endings, and released from nerve
by the sympathetic nervous system. Moreover, as described endings where they bind to various ion channel or G protein-
by Saper (225) activation of receptors in visceral organs can coupled receptors (GPCR) located on other neurons, smooth
impact more than autonomic target organs; for example, acti- muscle cells, or glandular cells to initiate their characteristic
vation of visceral receptors can result in changes in higher actions. The actions of the ACh and NE are terminated when
brain function including the limbic cortex to integrate auto- the transmitter is removed from the area by metabolism or
nomic function with ongoing behavior and emotions. reuptake. Each of these steps can be facilitated or depressed
As reviewed by Janig (143), these visceral sensory fibers with rather predictable consequences. ACh released from pre-
have a wide-range of functions including mediating protective ganglionic nerve terminals acts primarily on nicotinic recep-
reflexes, signaling visceral pain, and neuroendocrine regula- tors in the autonomic ganglia to excite postganglionic sympa-
tion. thetic and parasympathetic neurons; and ACh released from
Several articles within Comprehensive Physiology postganglionic parasympathetic nerves and some sympathetic
describe the role of these visceral afferent fibers in the control nerves acts on muscarinic receptors in non-neuronal auto-
of some autonomic target organs, including the heart, kidney, nomic effector organs (38, 116, 156, 216). NE released from
and the urinary tract (69, 94, 137, 147). Also, Guyenet (125) most sympathetic postganglionic nerves acts primarily on
has reviewed the critical role of receptors in the vasculature α- and β-adrenoceptors in target organs (38, 116, 156, 216).
(baroreceptors and chemoreceptors) that relay information Table 4 shows the types of cholinergic and adrenergic recep-
via the glossopharyngeal and vagus nerves to maintain car- tors at various junctions within the peripheral components
diorespiratory function. These articles can be consulted for of the ANS. Table 5 includes a list of the actions of various
details regarding the types of sensory receptors within vis- drugs that affect different steps within autonomic neurotrans-
ceral organs, the types of sensory fibers and their central mission. This table also points to the fact that many commonly
projections, and their role in mediating changes in autonomic used prescription drugs, over-the-counter drugs, toxins, and
function in health and disease. Also, Christianson and Davis toxicants impact autonomic function.
(62) have reviewed the literature regarding the role for changes The cholinergic autonomic neurons (i.e., neurons that syn-
in visceral afferents that contribute to visceral pain as well as thesize and release ACh onto their postsynaptic target) include
the development of various pathologies including diabetes, (1) all preganglionic neurons, (2) all parasympathetic postgan-
pancreatic cancer, and pancreatitis. glionic neurons, (3) sympathetic postganglionic neurons that
innervate sweat glands, and (4) sympathetic postganglionic
neurons that terminate on blood vessels in some skeletal mus-
Chemical Neurotransmission at cles of some species (e.g., cat) and produce vasodilation when
Autonomic Neuroeffector Junctions: ACh stimulated (sympathetic vasodilator nerves).
and NE The majority of sympathetic postganglionic neurons are
noradrenergic (i.e., neurons that synthesize and release NE
Neurotransmission at the synaptic junction between a pregan- onto their postsynaptic target). Also, the adrenal medulla,
glionic and a postganglionic neuron and between a postgan- which is analogous to a sympathetic postganglionic neuron
glionic neuron and its effector organ is chemically mediated. without an axon, synthesizes and releases a mixture of NE and
Either ACh or NE is the dominant autonomic neurotransmit- epinephrine. The ratio of these two chemicals released from
ter at most if not all of these synapses. There is evidence that the adrenal medulla varies among different species (143).
an individual sympathetic neuron can synthesize both NE and For example, the ratio of NE to epinephrine release from the
ACh, at least early in development (130). Early in develop- adrenal medulla is approximately 1:4 in humans and rats,
ment some neurons in the superior cervical ganglion have 3:2 in cats, and 3:7 in chickens. At the two extremes, the

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Table 4 Effector Organ/Tissue Responses to Activation of the Autonomic Nervous System

Parasympathetic nervous system Sympathetic nervous system


Organ/tissue Receptor Effector response Receptor Effector response

Eye
∙ Radial muscle α1 Contraction (mydriasis)
∙ Sphincter muscle M3 , M2 Contraction (miosis)
∙ Ciliary muscle M3 , M2 Contraction for near vision
∙ Ciliary epithelium β2 Aqueous humor secretion
∙ Lacrimal glands M3 , M2 Secretion βa Circulating epinephrine mediated-tear
production
∙ Salivary glands M3 , M2 Profuse watery secretion α1 , β Thick, viscous secretion
Respiratory tract
∙ Tracheal, bronchial smooth M2 = M3 Contraction β2 Relaxation
muscle
∙ Bronchial glands M3 , M2 ↑ Secretion α1 ↑ Secretions
β2 ↓ Secretions
∙ Nasopharyngeal glands M3 , M2 ↑ Secretion
Heart
∙ SA node M2 >> M3 ↓ Heart rate β1 > β2 ↑ Heart rate
∙ Atrial muscle M2 >> M3 ↓ Contractility β1 > β2 ↑ Contractility
∙ AV node M2 >> M3 ↓ Conduction velocity β1 > β2 ↑ Conduction velocity
∙ His-Purkinje system M2 >> M3 ↓ Conduction velocity β1 > β2 ↑ Conduction velocity
∙ Ventricular muscle β1 > β2 ↑ Contractility
Stomach and Intestine
∙ Smooth muscle M2 = M3 ↑ Motility and tone α1 , α2 , β2 ↓ Motility and tone
∙ Sphincter M3 , M2 Relaxation α1 Contraction
∙ Digestive glands M3 , M2 ↑ Secretions α2 ↓ Secretions
Gall bladder M Contraction β2 Relaxation
Kidney β1 ↑ Renin release
Liver α1 , β2 Glycogenolysis and gluconeogenesis
Spleen α1 Contraction
β2 Relaxation
Pancreas
∙ Acini M3 , M1 ↑ Amylase secretion
∙ Islets (β cells) M3 ↑ Insulin secretion α2 ↓ Insulin secretion
∙ Duct M3 , M2 ↑ HCO3 and fluid secretion

Genitourinary tract
∙ Detrusor muscle M3 > M2 Contraction β2 Relaxation
∙ Sphincter M3 > M2 Relaxation α1 Contraction
∙ Ureter M ↑ Motility and tone (?) α1 ↑ Motility and tone
∙ Uterus, pregnant M Variable α1 Contraction
β2 Relaxation
∙ Penis, seminal vesicles M3 Erection α1 Ejaculation
Skin
∙ Pilomotor muscles α1 Contraction
∙ Sweat glands M3 , M2 Secretion

(continued)

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Table 4 (Continued)

Parasympathetic nervous system Sympathetic nervous system


Organ/tissue Receptor Effector response Receptor Effector response

Arteries and Arterioles


∙ Coronary M3 Formation of NO, vasodilation α1 , α2 Constriction
β2 Dilation
∙ Skin and mucosa α1 , α 2 Constriction
∙ Skeletal muscle α1 Constriction
β2 , M3 Dilation
∙ Cerebral M1 Vasoconstriction α1 Modest constriction
M2 Vasodilation
M5 Activation of NO synthase
∙ Pulmonary α1 Constriction
β2 Dilation
∙ Viscera M3 Formation of NO, vasodilation α1 Constriction
β2 Dilation
∙ Salivary glands α1 Constriction
β2 Dilation
∙ Renal α1 , α 2 Constriction
β2 Dilation
Veins α1 , α 2 Constriction
β2 Dilation
Adipose tissue, white and brown β3 Lipolysis and thermogenesis
Pineal gland β Melatonin synthesis
Sympathetic nerve terminals
∙ Autoreceptors α2 ↓ NE release
β2 ↑ NE release
∙ Heteroreceptors M2 , M4 ↓ NE release
Parasympathetic nerve terminals
∙ Autoreceptors M2 , M4 ↓ ACh release
NN ↑ ACh release
∙ Heteroreceptors α2 ↓ ACh release
Skeletal muscle β2 K+ uptake, glycogenolysis

a Although there is minimal sympathetic innervation of the lacrimal glands, epinephrine released from the adrenal medulla can bind to β-
adrenoceptors on the glands to increase secretion of tears (72).

adrenal medulla of the whale and rabbit releases only NE and is transported from the extracellular space into the nerve ter-
epinephrine, respectively. As will be described below under minal via a high-affinity, Na+ -dependent choline transporter
Neurochemical Coding of Autonomic Neurons: Co-Release (203, 204). Uptake of choline into the nerve terminal is the
of Chemicals from Sympathetic and Parasympathetic Nerves, rate-limiting step in the synthesis of ACh, and hemicholin-
many autonomic neurons release other neurotransmitters or ium is a potent inhibitor of this choline uptake mechanism.
neuromodulators. The synthesis of ACh involves a single enzymatic reaction in
which choline acetyltransferase catalyzes the acetylation of
choline with acetyl coenzyme A (AcCoA). Following its syn-
Cholinergic neurotransmission: Acetylcholine thesis within the cytoplasm, ACh is transported from the cyto-
synthesis, storage, release, and degradation plasm into synaptic vesicles located within the nerve terminal
Figure 3 shows the biochemical events at a cholinergic auto- by a vesicular ACh transporter. This process is dependent on
nomic neuroeffector junction. ACh is stored in high concen- a proton-pumping ATPase that acidifies the vesicle. Once the
tration within small, clear synaptic vesicles in the terminals vesicle is acidified, the vesicular ACh transporter allows a
of cholinergic neurons (38, 156, 249). Choline that is needed proton within the vesicle to be exchanged for a molecule of
for the synthesis of ACh is readily available in the plasma and ACh. Vesamicol is a choline transport inhibitor, but it blocks

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Table 5 Pharmacological Approaches to Modifying Processes Involved in Transmission at Autonomic Neuroeffector Junctions

Transmission process Drug Site of drug action Drug Action

Neurotransmitter synthesis Hemicholinium Membrane of cholinergic nerve Blocks choline uptake, the
terminals rate-limiting step in the synthesis of
ACh; slows synthesis
Choline acetyltransferase inhibitor Cytoplasm of cholinergic nerve Blocks acetylation of choline with
terminals acetyl coenzyme A, the final step
in the synthesis of ACh
α-Methyltyrosine Cytoplasm of noradrenergic nerve Inhibits tyrosine hydroxylase, the
terminals rate-limiting step in catecholamine
synthesis
L-threo-3-4-dihydroxyphenylserine Cytoplasm of non-neuronal tissue Converted to NE by
(L-DOPS) and noradrenergic nerve L-aromatic-amino-acid
terminals decarboxylase (LAAAD)
Neurotransmitter storage Vesamicol Vesicles in cholinergic nerve Inhibits the vesicular ACh transporter,
mechanism terminals preventing storage of ACh
Reserpine Vesicles in noradrenergic nerve Inhibits the vesicular monoamine
terminals transporter, preventing storage of
catecholamines
Exocytosis/displacement of Latrotoxins Membrane of cholinergic nerve Forms pores on membrane surface to
neurotransmitter from terminals increase Ca2+ transport,
storage sites promoting ACh release
Botulinum toxin SNARE proteins on the membrane Blocks SNARE proteins, preventing
of cholinergic nerve terminals ACh release
Bretylium, guanethidine NET on noradrenergic nerve Prevents NE release
terminals
Neurotransmitter reuptake Cocaine, imipramine, NET on noradrenergic nerve Inhibits reuptake of NE; prolongs
mechanism methylphenidate, tricyclic terminals actions of neurotransmitter on
antidepressants postsynaptic adrenoceptors
Amphetamine NET on noradrenergic nerve Acts as both a NET substrate and
terminals reuptake blocker, causing reverse
transport and enhanced release of
NE
Neurotransmitter release NE, dopamine, acetylcholine Autoreceptors and heteroreceptors Modulates neurotransmitter release
mechanism on cholinergic and adrenergic
nerve terminals
Tyramine NET on noradrenergic nerve After entering the nerve terminal, it
terminals promotes an apparently
nonexocytotic release of NE
Inactivation of Edrophonium, neostigmine, AChE in cholinergic synapses Reversible inhibition of AChE;
neurotransmitter physostigmine, pyridostigmine prolongs and intensifies actions of
ACh
Malathion, parathion, sarin AChE in cholinergic synapses Irreversible inhibitor of AChE
α-Adrenoceptor activation α1 : Phenylephrine, methoxamine Sympathetic postganglionic Binds to and activates
α2 : Clonidine nerve-effector organ junctions α-adrenoceptors; ↑ IP3 /DAG
(e.g., blood vessels, hair cascade (α1 ) or ↓ cAMP (α2 )
follicles, and radial muscle)
β-Adrenoceptor activation β1 , β2 : Isoproterenol Sympathetic postganglionic Binds to and activates
β1 : Dobutamine nerve-effector organ junctions β-adrenoceptors; ↑ cAMP
β2 : Albuterol, salmeterol, (e.g., heart, bronchial smooth
terbutaline muscle, and uterine smooth
muscle)
α-Adrenoceptor blockade α1 , α2 : Phentolamine Sympathetic postganglionic Reversibly binds to and blocks
α1 : Doxazosin, prazosin, nerve-effector organ junctions α-adrenoceptors
tamsulosin, terazosin (eg, blood vessels)
α2 : Idazoxan, yohimbine
α1 , α2 : Phenoxybenzamine Sympathetic postganglionic Irreversibly binds to and blocks
nerve-effector organ junctions α-adrenoceptors
(e.g., blood vessels)

(continued)

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Table 5 (Continued)

Transmission process Drug Site of drug action Drug Action

β-Adrenoceptor blockade β1 , β2 : Propranolol Sympathetic postganglionic Reversibly binds to and blocks


β1 > β2 : Atenolol, esmolol, nerve-effector organ junctions β-adrenoceptors
metoprolol,nadolol, timolol (e.g., heart and bronchial
smooth muscle)
Nicotinic receptor activation ACh, carbochol, lobeline, nicotine Receptors on autonomic ganglia Binds to nicotinic receptors; opens
Na+ , K+ channels in postsynaptic
membrane
Nicotinic receptor blockade α-Conotoxin, hexamethonium, Receptors on autonomic ganglia Binds to and blocks nicotinic
mecamylamine, trimethaphan receptors
Muscarinic receptor ACh, bethanecol, methacholine, Cholinergic receptors on smooth Binds to and activates M1 -M5
activation pilocarpine muscle, cardiac muscle, and receptors; ↑ IP3 /DAG cascade or
glands ↓ cAMP
Muscarinic receptor Atropine, ipratropium, Cholinergic receptors on smooth Reversibly binds to and blocks
blockade scopolamine, tropicamide muscle, cardiac muscle, and M1 -M5 receptors
glands
Tolterodine, oxybutynin Moderately selective blockade of M3
receptors

ACh, acetylcholine; AChE, acetylcholinesterase; cAMP, cyclic adenosine monophosphate; IP3 /DAG, inositol 1,4,5-triphosphate and diacylglycerol;
NE, norepinephrine; NET, norepinephrine transporter; SNARE, soluble N-ethylmaleimide-sensitive-factor attachment protein receptor.

the evoked release of newly synthesized ACh from the vesi- its rapid removal from the synaptic cleft. Acetylcholinesterase
cle rather than the uptake and storage of ACh into the vesicle molecules are clustered in the postsynaptic membrane of
(203, 204, 249). cholinergic synapses. The breakdown of ACh to choline and
When an action potential is conducted toward the nerve acetate occurs within milliseconds at the neuromuscular junc-
terminal it activates an N-type voltage-gated Ca2+ channel tion, and the actions of ACh released at this junction are thus
which allows for an influx of Ca2+ into the nerve terminal rapidly terminated. The choline available from the hydroly-
(203, 204). This influx of Ca2+ leads to the docking, fusion, sis of ACh is available for reuptake into the nerve terminal,
and fission of the vesicle with the membrane of the nerve ter- allowing for the synthesis, storage, and release process to
minal. Vesicle-associated membrane proteins (VAMPs) pro- begin again.
mote the alignment of the vesicles with the release site on the
inner membrane of the nerve terminal. The release site con-
tains synaptosomal nerve-associated proteins (SNAPs) that Cholinergic receptors: nicotinic and muscarinic
interact with the VAMPS to allow for the release of ACh ACh released from nerve terminals acts on one of two types
via exocytosis from the synaptic vesicle into the synaptic of cholinergic receptors located on the membrane of the post-
cleft. Botulinum toxin interacts with the VAMPS and SNAPs synaptic target, which is another neuron in the case of the
and prevents the docking of vesicles to the nerve termi- autonomic ganglia and the CNS; or smooth muscle, glands,
nal membrane and thus preventing release of ACh into the or the heart (autonomic effector organs); or skeletal muscle
synaptic cleft. Botulinum toxins can impair transmission in (somatic nerve targets). The two types of cholinergic recep-
autonomic cholinergic synapses; for example, it inhibits the tors are called nicotinic and muscarinic, based historically on
release of ACh from parasympathetic fibers in the urinary their respective responses to the alkaloids, nicotine and mus-
bladder and has been used to treat bladder hyperactivity (238). carine, respectively. Sir Henry Dale (65) noted that the actions
Autonomic signs of botulism include constipation, urinary of ACh to reduce blood pressure and to promote release from
retention, orthostatic hypotension, and reduced salivation and exocrine glands resembled those of the alkaloid muscarine, a
lacrimation (61). In the case of blockade of ACh at the neuro- toxin derived from the mushroom Amanita muscaria. Thus,
muscular junction, flaccid paralysis of skeletal muscle occurs. he coined the term “muscarinic” to describe these actions of
This is the mechanism by which botulinum toxin (BOTOX® ) ACh. As early as 1869, it was known that atropine antag-
has therapeutic effects in the treatment of spasticity, muscle onized the effects of muscarine (153); atropine remains a
spasms, and rigidity (121). standard pharmacological approach to interrupt muscarinic
The ACh released from the nerve terminal can bind cholinergic neurotransmission (81). Dale also noted that the
to postsynaptic or presynaptic cholinergic (muscarinic or stimulatory actions of ACh on autonomic ganglia and skeletal
nicotinic) receptors or to the enzyme acetylcholinesterase muscle mimicked those of nicotine. Thus, he used the term
(38,156,249). The binding of ACh to the enzyme accounts for “nicotinic” to describe these actions of ACh. In 1889, Langley

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Comprehensive Physiology Overview of the ANS

Cholinergic effector junction

Action potential

AcCoA
+
Choline
ACh H+
Vesicular Choline
transporter H+ transporter
Ca2+ Ca2+ ATP
ACh ADP
ATP, P Na+
+
Choline
VAMPs
3Na+

ATP

Hetero ADP 3Na+


receptors Na+ 2K+
M2 NN
ATP, P M1 Na+/K+
ACh ATPase
ACh
SNAPs
Na+
ACh ACh

Choline
ACh +
Acetate
ACh
Effector
cells

M1
M2 NN Acetylcholine
M3 M4 M5 esterase
Muscarinic Nicotinic
receptors receptors

Figure 3 The biochemical events at a cholinergic autonomic neuroeffector junction such as autonomic ganglia,
smooth muscle, glands, or the heart. Choline is transported into the presynaptic nerve terminal by a Na+ -dependent
choline transporter. ACh is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltrans-
ferase (ChAT). ACh is transported from the cytoplasm into vesicles by the vesicular transporter along with peptides
(P) and adenosine triphosphate (ATP). ACh is released from the nerve terminal in response to an action potential-
mediated influx of Ca2+ . This causes the vesicles to fuse with the surface membrane; vesicle-associated membrane
proteins (VAMPs) promote the alignment of the vesicles with the release site on the inner membrane of the nerve termi-
nal. ACh and cotransmitters are released into the synaptic cleft via a process that includes synaptosome-associated
proteins (SNAPs). The released ACh can act on muscarinic (M1 -M5 ) G protein-coupled receptors on the postsy-
naptic target (e.g., smooth muscle) or on nicotinic ionotropic receptors in autonomic ganglia (NN ). In the synaptic
junction, ACh is readily metabolized by the enzyme acetylcholinesterase. Autoreceptors and heteroreceptors on
the presynaptic nerve ending modulate neurotransmitter release.

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and Dickinson (163) reported that curare caused “paralysis” responses elicited by the binding of ACh to these muscarinic
of autonomic ganglia, similar to its long-established fact that receptors are blocked by atropine.
it caused skeletal muscle paralysis as well. There are five subtypes of muscarinic receptors (M1 − M5 )
Nicotinic receptors are subdivided into those located on which are encoded by five distinct genes (81). Only M1 − M3
the endplate of the neuromuscular junction in skeletal muscle receptors are found at autonomic synapses. As listed in
(NM ) and those found in the CNS and autonomic ganglia (NN ). Table 6, these three receptor subtypes differ in terms of their
Nicotinic receptors are members of a superfamily of ligand- cellular responses and/or their anatomical location. All three
gated ion channels (ionotropic receptors) that also includes subtypes activate the mitogen-activated protein kinase path-
GABA-A, glycine, and some glutamate receptors. Table 6 way, but the type of G protein involved in mediating their
summarizes some of the properties of NM and NN receptors, actions can differ. M1 and M3 cholinergic receptors are cou-
including their location, cellular and molecular mechanisms, pled to Gq activation of phospholipase C and production of
and membrane and postsynaptic target responses (38,93,156, diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3),
216) Each nicotinic cholinergic receptor has five subunits that an increase in intracellular Ca2+ , and a slow EPSP in the
form a central channel through which the passage of Na+ and target organ or tissue. M2 cholinergic receptors are coupled
other cations occurs when the receptor is activated. The five to Gi and Go which inhibit adenylyl cyclase and reduce
subunits come from several types designated as α, β, γ, δ, intracellular cyclic adenosine monophosphate (cAMP); M2
and ε that are each coded by different genes. When an ACh receptors also regulate G protein-activated inward rectify-
molecule binds to the α-subunit of the nicotinic receptor, there ing K+ (GIRK) channels. M1 receptors are found in auto-
is a conformational change in the protein allowing the channel nomic ganglia and in some glands. M2 and M3 cholinergic
to open. This leads to an increase in Na+ conductance; the receptors are the dominant subtypes of muscarinic receptors
resulting influx of Na+ produces a depolarizing potential. NN found on autonomic target organs. M2 cholinergic recep-
cholinergic receptors have a high permeability to Ca2+ . tors are often called “cardiac” receptors since they are pri-
The responses produced in postganglionic neurons by marily found in the heart. They are also located on auto-
stimulation of their preganglionic innervation include both an nomic nerve terminals where they regulate neurotransmitter
initial rapid depolarization, the fast excitatory postsynaptic release (see below under Presynaptic Autoreceptors and Het-
potential (fast EPSP), and a delayed and prolonged excita- eroreceptors Modulate Neurotransmitter Release at Cholin-
tory postsynaptic potential (slow EPSP). The fast EPSP is ergic and Adrenergic Synapses). M3 cholinergic receptors
produced by ACh acting on the NN receptor and is responsi- are called “glandular or smooth muscle” receptors since
ble for generation of an action potential in the postganglionic they are prominent in exocrine glands and on smooth mus-
neuron. The slow EPSP is produced by ACh acting on a mus- cle. Tables 4 and 6 describe some of the major autonomic
carinic (M1 ) receptor on the membrane of the postganglionic functional responses resulting from activation of muscarinic
neuron and may modulate transmission through autonomic receptors.
ganglia.
The contraction of skeletal muscle elicited by the bind-
ing of ACh to NM receptors is readily blocked by drugs such Noradrenergic neurotransmission: Norepinephrine
as D-tubocurarine, the active component of curare, or gal- synthesis, storage, release, and degradation
lamine triethiodide. Transmission in autonomic ganglia is As will be described below under Indices of Autonomic Activ-
mediated primarily by the actions of ACh on NN receptors ity, measurement of plasma catecholamines and their deriva-
that are readily antagonized by drugs such as the long-acting tives has been used as a global index of sympathetic nervous
hexamethonium and the short-lasting trimethaphan. Although system activity in humans and animal models (89, 116, 271).
no longer used for therapeutic purposes, ganglionic blocking Therefore, it is important to understand the steps involved
agents were one of the first pharmacological treatments for in the synthesis and metabolism of NE. Figure 4 shows the
hypertension beginning in the 1950s (76, 250). The adverse biochemical events at a noradrenergic synapse. Most sym-
side effects included blurred vision, dry mouth, constipation, pathetic postganglionic neurons are noradrenergic; i.e., they
urinary retention, and impotence along with postural hypoten- synthesize and release NE. There are also many noradrenergic
sion. neurons in the brain, including the locus coeruleus and cau-
Muscarinic receptors are members of the large family of dal ventrolateral medulla. Central catecholaminergic neurons
GPCR (57, 81, 153, 154, 216), which are also referred to as 7- are known to contribute to central autonomic regulation, and
transmembrane domain receptors, heptahelical receptors, or the functions of such neurons are the subject of other review
serpentine receptors. The typical structural characteristics of articles (31, 125, 169).
GPCR include seven hydrophobic, transmembrane domains, When describing the synthesis, storage, release, and
an extracellular N-terminus, and an intracellular C-terminus. metabolism of NE, it is virtually impossible to separate this
The most commonly studied muscarinic receptors are those from the same processes of the other two principal cate-
located on autonomic effector organs innervated by postgan- cholamines found in the body, epinephrine and dopamine
glionic parasympathetic and some sympathetic fibers. The (38,116,156,216). To begin with, these catecholamines all use

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Table 6 Autonomic Cholinergic and Adrenergic Receptor Characteristics

Receptor
subtypes Location Molecular/cellular responses Functional responsesa

Cholinergic receptors
NN Autonomic ganglia; adrenal medulla ↑Na+ , K+ permeability Depolarization of postganglionic neuron;
secretion of epinephrine and NE from
adrenal medulla; pre- and postsynaptic
excitation; prejunctional release of
neurotransmitters
NM Endplate of the neuromuscular ↑Na+ , K+ permeability Depolarization of the motor endplate; skeletal
junction muscle contraction
M1 Autonomic ganglia, glands Coupled to Gq/11 to activate PLC; ↑ May contribute to transmission in autonomic
IP3 /DAG; ↑ Ca2+ ; slow EPSP; ↓ K+ ganglia; ↑ secretion from glands
conductance; activates PLD, PLA; ↑ AA
M2 Heart; smooth muscle; autonomic Coupled to Gi /Go to inhibit adenylyl ↓ Neural transmission; slows spontaneous
nerve terminals cyclase, ↓ cAMP; activates inwardly depolarization of sino-atrial node to ↓ heart
rectifying K+ channels; inhibits rate; ↓ conduction velocity in
voltage-gated Ca2+ channels; atrial-ventricular node; ↓ refractory period
hyperpolarization and contraction of atrial muscle; contraction
of smooth muscle; ↓ transmitter release via
activation of autoreceptors (cholinergic
nerve terminals) or heteroreceptors
(adrenergic nerve terminals)
M3 Smooth muscle, glands Same as M1 Contraction of smooth muscle; ↑ secretions
from glands; synthesis of nitric oxide
Adrenergic receptors
α1A Blood vessels, heart, lung, liver, Coupled to Gαq ; activates PLC; ↑ Vasoconstriction; promotes cardiac growth
smooth muscle, vas deferens, IP3 /DAG; ↑ Ca2+ , PKC; ↑ Na+ /H+ and structure
prostate exchanger; modulates K+ channels; ↑
MAPK signaling
α1B Heart, kidney, lung, spleen Same as α1A Promotes cardiac growth and structure;
cardiac remodeling
α1D Aorta, coronary artery, platelets, Same as α1A Vasoconstriction of aorta and coronary artery
prostate
α2A Autonomic ganglia, coronary and Coupled to Gαi and Gαo ; inhibits adenylyl Inhibition of sympathetic neurons;
CNS vessels, pancreas, platelets, cyclase, ↓ cAMP, ↓ PKA activity vasoconstriction of small vessels in skeletal
sympathetic neurons muscle; involved in the central components
of the baroreceptor reflex
α2B Blood vessels, coronary and CNS Same as α2A Predominant receptor subtype for α2 -mediated
vessels, kidney, liver, pancreas, vasoconstriction (nonsynaptic sites)
platelets, sympathetic neurons
α2C Presynaptic sympathetic nerve Same as α2A ↓ Neurotransmitter release and release from
terminals adrenal medulla
β1 Heart, kidney, adipocytes; skeletal Activates adenylyl cyclase, ↑ cAMP, ↑ PKA Positive inotropic and chronotropic actions in
muscle activity; activates L-type Ca2+ channels the heart; renin release
β2 Blood vessels, bronchi, eye, Same as β1 Relaxation of bronchial, gastrointestinal, and
gastrointestinal tract, heart, kidney, uterine smooth muscles; reduce secretions
lung; skeletal muscle from bronchial glands; vasodilation;
aqueous humor production; skeletal muscle
glycogenolysis and hypertrophy
β3 Adipose tissue Same as β1 Metabolism; lipolysis in adipocytes and
thermogenesis

AA, arachidonic acid; cAMP, cyclic adenosine monophosphate; CNS, central nervous system;IP3 /DAG, inositol 1,4,5-triphosphate and diacyl-
glycerol; MAPK, mitogen-activated protein kinase; PKA (C), phosphokinase A (C); PLA (C,D), phospholipase A (C, D).
a See Table 4 for additional functional responses. Also see Tank and Wong (247) for additional information for subtypes of adrenoreceptors.

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Adrenergic effector junction


Synapse en passant
Action potential

Hetero
Ca2+ receptors
DOPA DA NE
Ca2+
VMAT NE
Tyrosine
DA NE
ATP, NPY
NET

VAMPs β2
Tyrosine
transporter
NE

NPY
P1 α2 NE
NE Y2
ATP
ATP
NPY
Adenosine NE
ADP NPY
SNAPs
ATP NE
AMP NPY

Effector
organs

Purinergic Peptidergic Adrenergic


receptors receptors receptors

Figure 4 The biochemical events at a noradrenergic sympathetic neuroeffector junction such smooth muscle,
glands, or the heart. Tyrosine is transported into the nerve terminal by a tyrosine transporter. See Figure 5 for the
sequential steps involved in the conversion of tyrosine to 3,4-dihydroxy-l-phenylalanine (DOPA) to dopamine
(DA) to NE. DA is transported from the cytoplasm into the vesicle by the vesicular monoamine transporter
(VMAT) and is then converted to NE in the vesicle. NE is released from the nerve terminal in response to an
action potential-mediated influx of Ca2+ ; vesicles then fuse with the surface membrane to trigger expulsion of
NE and cotransmitters such as ATP and neuropeptide Y (NPY). The process involves SNAPs and VAMPs. The
released NE and cotransmitters can act on either G protein-coupled or ligand-gated ion channel receptors on
the sympathetic neuroeffector organ. NE can also diffuse out of the cleft or be transported back into the nerve
terminal by the NET. Transmitter release is modulated by autoreceptors and heteroreceptors on the presynaptic
nerve terminal.

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H H tyrosine as their source (Fig. 5). Tyrosine is an essential amino


HO C C NH2

H COOH
acid that is primarily made available for the synthesis of cate-
Tyrosine cholamines through diet. A Na+ -dependent carrier promotes
Tyrosine the transport of tyrosine into the cytoplasm of catecholamin-
hydroxylase ergic neurons. The enzyme tyrosine hydroxylase converts
HO tyrosine to 3,4-dihydroxy-l-phenylalanine (DOPA); this is
H H
HO C C NH2 the rate-limiting step in catecholamine synthesis. Tyrosine
H COOH hydroxylase is subject to feedback inhibition by dopamine and
DOPA NE, thus providing internal control of the synthetic process.
Aromatic-L-amino Metyrosine, once used as an antihypertensive drug, blocks
acid decarboxylase
the action of tyrosine hydroxylase and thus reduces levels of
HO
H H catecholamines in the body.
HO C C NH2
The next step in the synthesis of catecholamines is the
H H

Dopamine
conversion of DOPA to dopamine in the cytoplasm of the
cells (38, 116, 156, 216). This requires the action of aromatic
Dopamine
β-hydroxylase l-amino acid decarboxylase which is also called DOPA decar-
HO
H H HO
boxylase. Dopamine is then transported into the synaptic vesi-
H H H
HO C C NH2 Phenylethanolamine
HO C C N
cle by the vesicular monoamine transporter (VMAT) where
N-methyltransferase
OH H
OH H CH3 it is then converted to NE by the membrane-bound dopamine
Norepinephrine Epinephrine
MAO MAO β-hydroxylase (DBH). NE is the only small-molecule trans-
COMT COMT mitter that is synthesized in synaptic vesicles instead of being
HO transported into the vesicle after its synthesis. DBH is also
H O
CH3O CH3O
H H HO C C H H H H present in chromaffin cells of the adrenal medulla where it
HO C C NH2 OH H HO C C N converts dopamine to NE. Reserpine, also once used as an
OH H OH H CH3
DOPEGAL antihypertensive drug, blocks VMAT to prevent the move-
Normetanepinephrine Metanephrine
AR AD ment of dopamine into the synaptic vesicle and thus reduces
NE synthesis. Prolonged use of reserpine results in depletion
HO HO
H OH H O of NE stores, thus leading to a chemical sympathectomy.
HO C C H HO C C OH
Chromaffin cells within the adrenal medulla and some
OH H OH H

DHPG DHMA
neurons in the brain stem contain the cytoplasmic enzyme
phenylethanolamine-N-methyltransferase (PNMT), which
COMT
catalyzes the conversion of NE to epinephrine. When NE
CH3O
H OH
leaves the synaptic vesicles of these cells, it is converted to
HO C C H epinephrine in the cytoplasm; epinephrine is then transported
OH H
into other synaptic vesicles where it is stored until its release
MHPG
by exocytosis.
ADH AR Catecholamines are stored within both small, clear vesi-
cles and large, granular or dense-core vesicles in cate-
CH3O
MAO H O
MAO cholaminergic neurons (38,116,156,216). As discussed above
HO C C H
and illustrated in Figure 4, the axons of sympathetic post-
OH
MOPEGAL ganglionic neuron has multiple varicosities containing these
AD
synaptic vesicles along its course (synapse en passant), and
each of these varicosities is a site at which NE can be released
CH3O
H O via exocytosis. In response to an action potential reaching the
HO C C OH

OH
VMA

Figure 5 Steps involved in the synthesis and metabolism of cat- 


echolamines. The enzymes involved in the synthesis of DOPA, Figure 5 (Continued) MHPG is converted to 3-methoxy-4-
dopamine, NE, and epinephrine from tyrosine are shown in green. hydroxyphenylglycolaldehyde (MOPEGAL) by an alcohol dehydro-
The two enzymes involved in the degradation of catecholamines genase (ADH). MOPEGAL is then converted to vanillylmandelic acid
are monoamine oxidase (MAO) and catechol-O-methyltransferase (VMA) by AD; VMA is the most plentiful catecholamine metabolite
(COMT). MAO converts NE and epinephrine to a reactive intermedi- in the urine of humans. A minor pathway involved in the formation
ate aldehyde metabolite, 3,4-dihydroxyphenylglycolaldehyde (DOPE- of VMA includes the action of COMT to convert NE (or epinephrine)
GAL) which is then converted via an aldehyde reductase (AR) to to normetanephrine (or metanephrine) which is then converted to
3,4-dihydroxyphenylglycol (DHPG) or via an aldehyde dehydroge- MOPEGAL by MAO. The thickness of the red lines signifies the
nase (AD) to 3, 4-dihydroxymandelic acid (DHMA). DHPG is then importance of the metabolic step.
converted to 3-methoxy,4-hydroxyphenylglycol (MHPG) by COMT.

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nerve endings, there is an influx of Ca2+ via voltage-sensitive in sympathetic nerve terminals, metabolism of NE occurs
Ca2+ channels. The synaptic vesicle then fuses to the mem- independently of its exocytotic release into the synaptic cleft.
brane and releases NE or other catecholamines along with Vesicular stores of catecholamines should be considered to
ATP, neuropeptide Y (NPY), and other peptides. The synap- exist in a dynamic equilibrium with catecholamines in the
tic vesicles then undergo endocytosis and recycling. surrounding cytoplasm (83, 116). The other major metabolic
NE spreads farther and has a more prolonged action than enzyme, COMT, is also widely distributed, particularly in
ACh. Unlike ACh, NE, epinephrine, and dopamine are all the liver, kidneys, and smooth muscles. COMT is also found
found in plasma. Epinephrine and some of the dopamine come in glia within the brain, and small amounts of it are found in
from the adrenal medulla; while some of the NE is released postsynaptic neurons. Presynaptic noradrenergic neurons in
from the adrenal medulla, most of the NE diffuses into the the brain are devoid of COMT.
bloodstream from sympathetic nerve endings. Metabolites A 2004 review by Eisenhofer and colleagues (83) cor-
of NE and dopamine also enter the circulation. The role of rects some common misconceptions that continue to appear
dopamine, its precursor (L-dopa), and its metabolites in con- in some textbooks and review articles on the topic of cat-
trol of renal function and blood pressure is discussed in other echolamine metabolism. NE and epinephrine are metabo-
articles within Comprehensive Physiology (11). As will be lized to biologically inactive products by a combination of
described below under Indices of Autonomic Activity, plasma oxidative deamination, aldehyde dehydrogenase, and alde-
levels of catecholamines and their metabolites are used as an hyde reductase (Fig. 5). As a first step, MAO converts NE
index of the level of sympathetic nerve activity. and epinephrine to a reactive intermediate aldehyde metabo-
Several processes contribute to the removal of NE from the lite, 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). An
synaptic cleft. These include binding to postsynaptic adreno- aldehyde dehydrogenase can then metabolize DOPEGAL to
ceptors to elicit its actions on target tissue and organs, binding an acid metabolite 3, 4-dihydroxymandelic acid (DHMA).
to presynaptic adrenoceptors to modulate neurotransmitter This is often mistakenly featured as the main end-product
release, reuptake into the presynaptic neuron, or enzymatic of the breakdown of DOPEGAL. Rather, the presence of a
degradation. Reuptake into the neuron is mediated by a NE β-hydroxyl group on NE and epinephrine and their deami-
transporter (NET) and is the major mechanism by which the nated metabolite DOPEGAL favors another metabolic path-
actions of NE are terminated at catecholaminergic synapses. way. Specifically, an aldehyde reductase or a related enzyme
Following its exocytosis, NE diffuses toward the NET on called aldose reductase metabolizes DOPEGAL to the alco-
the presynaptic nerve terminal, allowing NE to be pumped hol metabolite 3,4-dihydroxyphenylglycol (DHPG). In sym-
back into the nerve terminal against its concentration gradi- pathetic neurons and adrenal medullary chromaffin cells, the
ent. This process relies on the co-transport of Na+ and Cl− ; aldose reductase is the major enzyme involved in converting
the Na+ gradient in the membrane is maintained by Na+ , K+ - DOPEGAL to DHPG. A similar multi-step process is involved
ATPase. Cocaine and tricyclic antidepressants block the NET in the metabolism of dopamine, but the final end-product is
to increase circulating levels of catecholamines. the acid metabolite. MAO first converts dopamine to 3,4-
Several drugs can also be transported into the noradren- dihydroxyphenylacetaldehyde (DOPAL) which is then metab-
ergic nerve terminal via NET and result in a reduction in NE olized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC)
release. Two examples are bretylium and guanethidine. When by the aldehyde dehydrogenase or, less commonly, to the
taken up by a noradrenergic nerve terminal, bretylium was alcohol metabolite 3,4-dihydroxyphenylethanol (DOPET) by
thought to exert its effect by abolishing the action potential in the aldehyde reductase.
the nerve terminal; however a recent study (33) showed that Vanillylmandelic acid (VMA) is the most plentiful cat-
it can inhibit NE release by an action downstream of Ca2+ echolamine metabolite in the urine of humans. Typically
influx without preventing the nerve terminal action poten- urinary levels of VMA are low but increase during stress.
tial. Bretylium has been used as an antiarrhythmic drug, Very high levels can be an indicator of pheochromocy-
but as of 2011 it is no longer marketed for clinical use. tomas, neuroblastomas, or neuroendocrine tumors (83, 116).
Guanethidine is also transported into a noradrenergic nerve Although commonly thought to result from the O-methylation
terminal via NET; it is then sequestered in the synaptic vesi- of DHMA, as reviewed by Eisenhofer et al. (83), this
cles where it replaces NE and thus gradually depletes NE is not the case. Rather, VMA formation is primarily the
release (156). result of oxidation of 3-methoxy,4-hydroxyphenylglycol
The metabolism of catecholamines has been the subject of (MHPG) formed by O-methylation of DHPG via COMT.
much work for many years; and drugs acting on this process Specifically, COMT converts DHPG to MHPG in extra-
have been important in the treatment of neurological disor- neuronal tissue. MPHG is then converted to 3-methoxy-4-
ders (83, 116). As shown in Figure 5, two of the key enzymes hydroxyphenylglycolaldehyde (MOPEGAL) by an alcohol
involved in the degradation of catecholamines are monoamine dehydrogenase and subsequently to VMA via an aldehyde
oxidase (MAO) and catechol-O-methyltransferase (COMT). dehydrogenase in the liver. A minor pathway involved in the
MAO is located on the outer surface of the mitochondria formation of VMA includes the action of COMT to convert
and is in plentiful supply within the nerve endings from NE to normetanephrine which is then converted to MOPE-
which catecholamines are released. Since MAO is found GAL by MAO.

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α- and β-Adrenoceptors autoreceptors and adrenergic heteroreceptors (Fig. 3). When


an agonist binds to these receptors, release of ACh is mod-
NE and epinephrine act on families of α-and β-adrenergic
ulated. Specifically, an action of ACh on M2 receptors on
receptors (adrenoceptors) which are GPCRs with the typi-
cholinergic nerve terminals is to inhibit further release of ACh
cal seven hydrophobic, transmembrane domains, an extra-
onto autonomic effector organs; this is sometimes referred to
cellular N-terminus and an intracellular C-terminus. Molecu-
as autoinhibitory feedback (246). NN receptors function to
lar cloning has led to the identification of nine adrenocep-
facilitate release of neurotransmitter at cholinergic synapses
tor subtypes: α1A , α1B , α1D , α2A , α2B , α2C , and β1 − β3
in the CNS and at the neuromuscular junction and enteric ner-
which can vary in terms of the G protein activated after bind-
vous system (104, 265). NE can act on α2 -adrenoceptors on
ing of an agonist to the receptor (45, 247). Table 4 shows
cholinergic nerve terminals to inhibit further release of ACh
some of the locations of these receptor subtypes on smooth
onto postsynaptic target organs (6, 216).
muscles, cardiac muscle, and glands on autonomic effector
As shown in Figure 4, adrenergic nerve terminals possess
targets. Table 6 summarizes some of the major characteris-
adrenergic autoreceptors and cholinergic heteroreceptors that
tics of these receptors including their location, cellular and
modulate the release of NE (32, 114, 240, 241). As is the case
molecular mechanisms, and membrane and postsynaptic tar-
for cholinergic synapses, activation of presynaptic autore-
get responses (38, 216, 247). A recent review by Tank and
ceptors at adrenergic synapses can either facilitate or inhibit
Wong (247) goes into more detail regarding the GPCRs and
further release of NE. Specifically, activation of presynaptic
signaling pathways that characterize the various subtypes of
β2 -adrenoceptors (and perhaps β1 -adrenoceptors) increases
adrenoceptors.
release of NE, whereas activation of α2 -adrenoceptors inhibits
Most α1 -adrenoceptors are coupled via Gq/G11 proteins
further release of NE onto various sympathetic effector organs
which activate phospholipase C, leading to the formation
(23, 196, 240, 241). Cholinergic agonists acting on M2 het-
of IP3 and DAG, which mobilizes intracellular Ca2+ stores
eroreceptors on sympathetic nerve terminals inhibits the
and activates protein kinase C, respectively. Thus, at many
release of NE (56, 82). These receptors likely account for
synapses, activation of α1 -adrenoceptors is excitatory to the
the known inhibitory interactions of vagal and cardiac sym-
postsynaptic target. In contrast, α2 -adrenoceptors activate
pathetic nerves in control of cardiac function (253). There is
Gi /Go inhibitory proteins to inhibit adenylyl cyclase and
also evidence for M1 heteroreceptor-mediated enhancement
stimulate phospholipase A2 activities to decrease cAMP.
of NE release from sympathetic nerve terminals in various
Other actions of α2 -adrenoceptors are to activate GβΥ pro-
vascular regions (56).
tein coupled to inward rectifier K+ channels to cause mem-
Modulation of transmitter release from sympathetic and
brane hyperpolarization and to inhibit neuronal Ca2+ chan-
parasympathetic neurons is not limited to actions of choliner-
nels. Thus, at many synapses, activation of α2 -adrenoceptors
gic and adrenergic agonists. Boehm and Kubista (32) wrote an
inhibits the postsynaptic target. Presynaptic α2 -adrenoceptors
excellent review of the complexity of postganglionic sympa-
are autoreceptors which, when activated, inhibit further
thetic nerve terminals; more than 30 types of GPCRs and
release of NE from postganglionic sympathetic nerve termi-
four types of ligand-gated ion channels have been local-
nals (see the following section). All β-adrenoceptors activate a
ized to these nerve terminals. In addition to ACh and cate-
stimulatory GS protein to activate adenylyl cyclase to increase
cholamines, the following receptor agonists are among those
cAMP.
that can act on presynaptic heteroreceptors to modulate the
As shown in Table 4, α1 -adrenoceptors are dominant on
release of NE onto autonomic effector organs: adenosine,
smooth muscle of many if not most autonomic target organs,
angiotensin II, ATP, bradykinin, cannabinoids, dopamine,
whereas α2 -adrenoceptors are found primarily on the smooth
endothelin, GABA, glycine, histamine, NPY, opioids, sero-
muscle of the gastrointestinal tract and some blood vessels,
tonin, and somatostatin. Release of ACh from autonomic
on pancreatic islets cells, and on autonomic nerve terminals.
cholinergic neurons is inhibited by histamine or opioids acting
The β1 -adrenoceptors are dominant in the heart and renal
on presynaptic heteroreceptors (99, 227).
juxtaglomerular cells; β2 -adrenoceptors are found in the cil-
iary epithelium, on bronchial smooth muscle and glands, on
smooth muscle of the vasculature, and in skeletal muscle; and Neurochemical Coding of Autonomic
β3 -adrenoceptors are primarily located in adipose tissue.
Neurons: Co-Release of Chemicals from
Sympathetic and Parasympathetic
Presynaptic autoreceptors and heteroreceptors Nerves
modulate neurotransmitter release at cholinergic In 1935 Dale suggested that the same neurotransmitter was
and adrenergic synapses released at all synapses of a neuron (67). For the next 40+
Neurotransmitter release is modulated by activation of presy- years, this concept was mistakenly restated as a single neu-
naptic autoreceptors or heteroreceptors at cholinergic and ron releases only one neurotransmitter and was referred
adrenergic synapses (114,240,241,253). For example, cholin- to as “Dale’s Principle.” In the late 1970’s immunohisto-
ergic nerve terminals have both nicotinic and muscarinic chemical techniques began to provide substantial evidence

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that ACh and NE were not the only chemicals in auto- and it can undergo changes during development or dur-
nomic neurons, and by the 1980’s it was recognized that ing pathophysiological conditions. The following is a brief
co-transmission is more the norm than the exception in description of a few of the established examples of co-release
synaptic function (44, 179). This has been repeatedly demon- of substances from autonomic neurons.
strated for autonomic neurotransmission; many autonomic Preganglionic neurons that terminate in the superior cer-
neurons (both preganglionic and postganglionic neurons) con- vical ganglion have been the focus of many studies assess-
tain chemical messengers that can be co-released with ACh ing co-localization and co-release of chemicals with ACh
or NE (43, 86, 109, 111, 143, 179, 195, 202, 216). The exten- (150, 171). The superior cervical ganglion influences many
sive list of substances synthesized and/or released along with autonomic responses as it provides the sympathetic innerva-
ACh and/or NE includes adenosine, ATP, calbindin, calci- tion to all head and neck organs (e.g., cerebral circulation,
tonin gene-related peptide (CGRP), calretinin, cocaine- and choroid plexus, cranial muscle vasculature, eyes, lacrimal
amphetamine-regulated transcript (CART), corticotrophin glands, salivary glands, and pineal gland). In the majority
releasing factor (CRF), dopamine, dynorphin, endocannabi- of sympathetic preganglionic neurons that terminate in the
noids, GABA, galanine, 5-hydroxytryptamine (serotonin), superior cervical ganglion, NO is apparently co-localized with
NPY, neurotensin, nitric oxide (NO), nitric oxide synthase ACh allowing NO to have a role in regulating the level of sym-
(NOS), opioid peptides, pituitary adenylate cyclase-activating pathetic nerve activity emanating from this ganglion. NO has
peptide (PACAP), prostaglandins, somatostatin, substance P, been identified specifically within preganglionic fibers that
and vasoactive intestinal polypeptide (VIP). Whereas most innervate postganglionic neurons that control salivary secre-
classical neurotransmitters like NE and ACh are stored in tion and retraction of the upper eyelid (171).
small synaptic vesicles, peptides are typically found in large Boehm and Kubista (32) reviewed the evidence that many
dense-cored vesicles. The small molecule neurotransmitters of the substances co-released with NE from postganglionic
can be co-localized with peptides in these large dense-cored sympathetic nerve fibers act on receptors located on these
vesicles. nerve terminals to either increase or decrease NE release.
When co-released with NE or ACh, these chemicals can ATP, NE, and NPY can be stored within the same or differ-
either modulate or mediate neuroeffector responses induced ent synaptic vesicles within sympathetic postganglionic nerve
by activation of the sympathetic and parasympathetic neurons, terminals innervating the vasculature and visceral organs;
respectively. Although ACh acting on NN cholinergic recep- they are co-released in response to stimulation of sympathetic
tors is commonly thought to be the sole basis for the fast EPSP nerves (43, 44). NPY appears to act primarily by modulating
in autonomic ganglia, many populations of preganglionic neu- release of NE and ATP. The purinergic-mediated responses
rons express neuropeptides such as CGRP, substance P, and appear to be optimal with short bursts of low frequency
opioid peptides (112) as well as NOS and NO (131). The stimulation of sympathetic nerves while longer durations of
role of these co-transmitters in ganglionic neurotransmission higher frequency stimulation favor NE-mediated responses
remains somewhat speculative; for example, the co-release (235). Release of ATP from postganglionic sympathetic neu-
of ACh and substance P from a preganglionic neuron may rons acts on presynaptic ATP-gated ionotropic P2X receptors
enhance postganglionic neuronal excitability, and the release to increase NE release in the atrium, ear artery and ileum;
of opioid peptides may suppress further release of ACh from a but ATP can also act on presynaptic metabotropic G-protein-
preganglionic nerve terminal. Likewise, NO has been shown coupled P2Y receptors to reduce NE release in the atrium,
to exert both excitatory and inhibitory actions on nicotinic iris, kidney, pancreas, tail artery, and vas deferens (32).
transmission in prevertebral ganglia of the rabbit (215). ATP release is a critical factor for sympathetic stimulation-
The co-localization of one or more substance with the induced excitatory junctional potentials in vascular smooth
classical autonomic neurotransmitters is not random. Rather, muscle and smooth muscle of the vas deferens (43,44). When
work beginning in the 1980’s led to the discovery that there is a the effects of sympathetic nerve stimulation on vas deferens
relationship between the neurochemical phenotype and func- smooth muscle were first reported in 1960, it was evident
tion of autonomic neurons. Although sometimes referred to that adrenoceptor antagonists did not prevent these excitatory
as the non-adrenergic non-cholinergic (NANC) transmission, junctional potentials; however, guanethidine (a drug that pre-
the more desirable term of chemical coding or neurochemical vents the release of NE) was effective. An explanation for
coding is used to describe the coexistence of ACh or NE with this unexpected finding did not appear until about 20 years
another chemical or molecule in functional groups of pregan- later when desensitization of the ATP (P2) receptors with α,β-
glionic and postganglionic neurons (143, 171, 195, 202). methylene ATP blocked these excitatory junctional potentials
Table 7 provides a list of some of the known exam- in the vas deferens. The relative role of NE versus ATP in
ples of neurochemical coding within the sympathetic ner- mediating vasoconstriction varies among different vascular
vous system, especially as related to the coexistence of a beds (44). At one extreme, in the submucosal region of the
neuropeptide with a classical transmitter. The pattern of co- guinea pig ileum, ATP functions as the main neurotransmit-
release of chemicals from preganglionic and postganglionic ter responsible for vasoconstriction; and NE has the role of a
sympathetic nerve terminals varies among species and organs neuromodulator (90). On the other hand, in rat renal arteries,

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Table 7 Neurochemical Coding of Sympathetic Neurons

Functional neuronal group Neurochemical phenotype Species

Sympathetic preganglionic neurons controlling:


Salivary gland secretion ACh + calretinin Rat
Salivary gland secretion ACh + NOS Guinea pig
Upper eyelid retraction ACh + calretinin + enkephalin Rat
ACh + calbindin + encephalin
ACh + NOS
Heart rate and contraction ACh + calretinin + NOS Rat
Sweating Cat
Epinephrine release from adrenal medulla ACh + calretinin Cat
Vasoconstriction ACh + CGRP or enkephalin Guinea pig
Vasodilation ACh + substance P or enkephalin Guinea pig
Piloerection ACh + enkephalin Guinea pig
Sympathetic postganglionic neurons controlling:
Pupillary dilation NE + neuropeptide Y + dynorphin Guinea pig
Muscle and cutaneous vasoconstriction NE + galanine +NPY Cat
Muscle vasoconstriction NE + NPY Guinea pig
Muscle vasodilation ACh + VIP Cat
Muscle vasodilation ACh + VIP + NPY + dynorphin Guinea pig
Cutaneous vasoconstriction NE + NPY Guinea pig
NE + NPY + dynorphin
NE + dynorphin
Piloerection NE + galanine Cat
Piloerection NE + dynorphin Guinea pig
Gastrointestinal motility NE + somatostatin Cat

See references: (109, 143, 171); ACh, acetylcholine; NE, norepinephrine; NOS, nitric oxide synthase; NPY, neu-
ropeptide Y; VIP, vasoactive intestinal peptide.

ATP has essentially no effect on the degree of vasoconstric- on presynaptic autoreceptors is to reduce the amount of NE
tion (44). Rummery et al. (224) provided evidence that the released from these fibers (179, 181).
physiological importance of ATP in mediating vascular con- Neurochemical coding has also been identified in some
traction of small mesenteric vessels is increased as the intra- portions of the parasympathetic nervous system (110-112,
luminal pressure rises and suggested that this could contribute 143,178). For example, NO is co-localized with ACh in post-
to or exacerbate the elevated arterial pressure associated with ganglionic parasympathetic fibers innervating the lacrimal
hypertension. and salivary glands as well as cerebral blood vessels. Somato-
NPY is stored along with NE in large dense core vesicles in statin is co-localized with ACh in vagal fibers innervat-
sympathetic postganglionic fibers (98). High frequency stim- ing the heart. VIP is co-released with ACh on postgan-
ulation of the sympathetic nerve is likely needed to release the glionic parasympathetic fibers innervating several autonomic
NPY (180). The NPY released during 20-Hz stimulation led effector organs including the salivary glands, gastrointesti-
to a slow onset but prolonged pressor response in pithed rats nal smooth muscle, and vasculature of the penis. Lundberg
that persisted after blockade of adrenergic receptors (157). (178) showed that the ACh released by low frequency stim-
The NPY released from sympathetic nerves is regulated pre- ulation of the parasympathetic nerves to the salivary glands
junctionally by endogenous NE acting on α2 -adrenoceptors on increases in salivary secretion from acinar cells, whereas VIP
sympathetic nerve terminals; α2 -adrenoceptor agonists reduce is released during high frequency stimulation and primarily
NPY release and α2 -adrenoceptor antagonists enhance NPY causes vasodilatation of blood vessels. VIP can also serve as
release (179). Likewise, NPY regulates the release of NE a neuromodulator to enhance the actions of ACh on acinar
from sympathetic terminals; specifically, an action of NPY cells.

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Physiological Actions of Sympathetic In comparison, somatomotor nervous system control of skele-


tal muscle seems much simpler. When ACh is released from
and Parasympathetic Outflow: an α-motor neuron and binds to NM receptors at the neu-
Antagonistic, Synergistic, and romuscular junction, the increase in Na+ and K+ conduc-
tance generates an end plate potential which is the trigger
Independent Control of Target Organs for a series of events (an action potential in skeletal mus-
In addition to the direct effect of a neurotransmitter released cle, release of Ca2+ from the sarcoplasmic reticulum, and
by a sympathetic or parasympathetic nerve onto a receptor on formation of cross-linkages between actin and myosin) that
a target organ or tissue, several other factors need to be con- lead to the contraction of skeletal muscles (21). The relax-
sidered when assessing the actions of the ANS on that organ ation of these muscles is a passive process in that it depends
or tissue. One, as described above, there are adrenergic and simply on the silencing of the α-motor neuron. In contrast,
cholinergic receptors on the postganglionic nerve terminals ACh release from a parasympathetic nerve can be followed by
that modulate neurotransmitter release (Table 4). NE released either contraction or relaxation of different smooth muscles.
from sympathetic nerve terminals can act on both α2 - and β2 - One might think that this is simply because ACh acts on differ-
adrenoreceptors (autoreceptors) to reduce or enhance further ent types of muscarinic receptors. For example, M2 receptors
NE release. Activation of M2 and M4 cholinergic receptors are coupled to Gi /Go which inhibits adenylyl cyclase, reduces
(heteroreceptors) on these same nerve terminals reduces NE intracellular cAMP, opens inwardly rectifying K+ channels,
release; so in organs that receive dual innervation, the ACh inhibits voltage-gated Ca2+ channels, and leads to membrane
release from a parasympathetic nerve in the vicinity of a sym- hyperpolarization (relaxation). In contrast, M3 receptors are
pathetic nerve could decrease the amount of NE released from coupled to Gq which activates the inositol phosphate pathway
the sympathetic nerve terminal. Similarly, activation of α2 - to promote depolarization and a slow EPSP (contraction). But
adrenoreceptors (heteroreceptors) or M2 and M4 cholinergic this is not the explanation since ACh released by parasympa-
receptors (autoreceptors) on parasympathetic nerve terminals thetic nerve terminals can contract one type of smooth muscle
reduces ACh release. Two, the NE and epinephrine released (e.g., detrusor muscle) and can relax another (e.g., urethral
upon activation of the adrenal medulla has access to virtually sphincter) even though both types of smooth muscle express
all organs simultaneously. Three, autonomic effector organs M3 and M2 receptors, with the M3 being the dominant recep-
are under feedback control from a variety of reflexes (e.g., tor in both locations. In the case of at least some smooth
baroreflex, chemoreflex, exercise pressor reflex) which can muscles (including the urethral sphincter), the release of ACh
modify (reverse or enhance) the effects of direct stimulation from a parasympathetic nerve is accompanied by the synthesis
of autonomic input to an effector organ. Four, some effector or co-release of NO which mediates the relaxation of smooth
organs have non-innervated cholinergic (e.g., blood vessels) muscles (10, 95).
or non-innervated adrenergic (e.g., lacrimal glands) recep-
tors onto which circulating levels of a drug can bind and thus
induce a response. So, for example, epinephrine released from Sympathetic and parasympathetic nerves can
the adrenal medulla can bind to β-adrenoceptors to promote function as physiological antagonists
an increase secretion of proteins from the lacrimal gland of For some target organs under the control of the ANS, it is
mice (72). possible to shift from contraction to relaxation by switch-
As a result of innervating most of the organs and tis- ing between stimulation of the parasympathetic nerves and
sues within the body (except for skeletal muscle), it is not stimulation of the sympathetic nerves. This is the situation
unexpected that the ANS would regulate and coordinate a for those organs that receive dual innervation which func-
vast array of physiological functions. These include accom- tion as physiological antagonists, including airways, the gas-
modation for near vision, airflow through the bronchial tree, trointestinal tract, and the urinary bladder (see Table 4). The
blood flow, blood pressure, body temperature, gastrointestinal heart is another example of an organ with dual antagonistic
motility, glandular secretions, heart rate, metabolism, pupil- control, but in this case sympathetic nerve activity exerts an
lary diameter, salt and water balance, sexual physiology, and excitatory effect and parasympathetic nerve activity exerts an
urinary bladder contraction. Table 4 provides a list of the inhibitory effect on cardiac function. Specifically, the nerve
typical responses elicited by selective activation of the nora- terminals of sympathetic postganglionic neurons in the upper
drenergic (sympathetic) or cholinergic (parasympathetic or thoracic paravertebral ganglia release NE that binds to β1 -
sympathetic) postganglionic nerve fibers controlling many adrenoceptors on pacemaker cells, conducting tissue, and car-
target organs and tissues. diac muscle within the heart to induce tachycardia (positive
Several important factors contribute to the complexity of chronotropy), increased the speed of conduction through the
effector responses mediated by activation of the ANS. These atrioventricular node and ventricular Purkinje fibers (positive
include the fact that many organs or tissues are innervated dromotropy), and increased atrial and ventricular contrac-
by both parasympathetic and sympathetic nerves, that auto- tility (positive inotropy). The parasympathetic vagal effer-
nomic nerves release different neurotransmitters, and that a ent nerve terminals innervate cardiac postganglionic neurons
given neurotransmitter can act on different receptor subtypes. that release ACh that binds predominantly to M2 cholinergic

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receptors in the heart to mediate the opposite actions on heart mydriasis; parasympathetic fibers in the ciliary nerve release
rate, conduction through the atrioventricular node, and atrial ACh that acts predominantly on M3 cholinergic receptors on
contraction; however, ACh has little influence on ventricular the sphincter (or constrictor) muscle to mediate miosis.
contractility. It is worth mentioning that in most cases, physi- Another example of synergistic actions of sympathetic
ological stimuli do not simultaneously activate both divisions and parasympathetic nerves is the effects of the ANS on sex-
of the ANS to these organs. For example, stimuli such as ual function (9, 115). Release of ACh during activation of
baroreceptors that activate the parasympathetic input to the parasympathetic nerves to the trabecular arteries of the penis
heart simultaneously decrease sympathetic nerve activity to promotes the release of NO from endothelial cells which then
the heart. So the changes in the activity within the two divi- causes vasodilation and erection. Ejaculation is induced by
sions of the ANS actually work in concert to reduce the heart NE release from postganglionic sympathetic nerves from the
rate. inferior mesenteric ganglia acting on α1 -adrenoceptors to con-
tract the smooth muscle of the epididymis, vas deferens, sem-
Sympathetic and parasympathetic nerves can have inal vesicles, prostate gland, prostatic urethra, and bladder
complementary functions neck.
In the case of some physiological processes that are regu-
lated by both divisions of the ANS, the responses elicited by Sympathetic and parasympathetic nerves can
stimulation of the sympathetic and parasympathetic nerves function independently
are complementary rather than antagonistic. One example
Many organs or tissues receive input from only one division of
of this is the control of salivary secretions from the acinar
the ANS (Table 4). The lacrimal glands, ciliary muscles (for
cells (synthesis and release of proteins), ducts cells (fluid
accommodation for near vision), and nasopharyngeal glands
and electrolyte transport), and goblet cells (secretion of high-
are innervated exclusively by parasympathetic nerves. The
molecular weight glycoproteins called mucins) of the parotid,
adrenal medulla, most blood vessels, erector pili (pilomotor)
sublingual, and submandibular glands (77, 133, 210). Activa-
muscles in the skin, gallbladder, immune cells, kidney, pineal
tion of the parasympathetic pathways that originate in the
gland, and sweat glands are innervated exclusively by sym-
inferior and superior salivatory nuclei in the brainstem and
pathetic nerves. Although it is often claimed that the brown
synapse on postganglionic neurons close to these salivary
adipose tissue, liver, and spleen receive innervation from sym-
glands causes release of copious watery saliva via an action of
pathetic but not parasympathetic fibers, there is some evidence
ACh primarily on M3 cholinergic receptors. Likewise, activa-
that vagal efferent fibers from the dorsal motor nucleus of the
tion of the postganglionic sympathetic nerves from the supe-
vagus directly terminate in these structures (39). This is a
rior cervical ganglia to these glands produces a thick, viscous
somewhat atypical parasympathetic pathway in that it is not
(mucoid) salivary secretion via an action of NE on α1 -and β-
cholinergic and does not include a ganglionic connection.
adrenoceptors. Salivary secretion is also controlled indirectly
The NE released from postganglionic sympathetic fibers
by the ANS through regulation of the blood flow to sali-
supplying the vasculature (arteries, arterioles, and veins) of
vary glands. Sympathetic-mediated vasoconstriction reduces
most organs acts primarily on α1 -adrenoceptors to mediate
salivary flow; parasympathetic-mediated release of NO pro-
vasoconstriction and an increase in blood pressure. Many
motes vasodilation that contributes to an increase in salivary
blood vessels also have β2 -adrenoceptors which mediate
secretion. Another example of an organ that receives com-
vasodilation and a reduction in blood pressure. Epinephrine
plementary control is the pancreas (78, 108, 177). Activa-
release from the adrenal medulla is a potent stimulus of these
tion of both vagal parasympathetic fibers and sympathetic
receptors. The existence of vascular β2 -adrenoceptors is easily
nerves induces release of insulin from pancreatic islet β-cells
revealed when one compares the blood pressure response to an
(endocrine function of the pancreas); however, sympathetic
intravenous injection of epinephrine before and after block-
nerve activity appears to have minimal influence on release of
ade of α1 -adrenoceptors. Before blockade, the vasoconstric-
amylase via the acinar cells and fluid and electrolyte transport
tor action of epinephrine on the α1 -adrenoceptors is dominant
via the pancreatic ducts (exocrine functions of the pancreas).
and thus blood pressure increases. Following administration
of a α1 -adrenoceptor antagonist, the binding of epinephrine
Sympathetic and parasympathetic nerves can to β2 -adrenoceptors induces vasodilation and a fall in blood
function in a synergistic manner pressure. This effect is called the “epinephrine reversal” (38).
The sympathetic and parasympathetic divisions of the ANS In some species including humans and cats, blood vessels
can also act in a synergistic or cooperative manner in the in skeletal muscles of the limbs are innervated by sympa-
control of autonomic processes via their innervation of differ- thetic postganglionic fibers that release ACh that act on M3
ent effector organs. Control of pupil diameter in the eye is an cholinergic receptors to mediate vasodilation and increased
example. Activation of both sympathetic and parasympathetic blood flow (134, 141, 189). Thus they are called sympathetic
nerves causes contraction of a pupillary muscle. Sympathetic cholinergic vasodilator fibers, and their effects on blood flow
fibers from the superior cervical ganglia release NE that acts are blocked by atropine (141). This vasodilation is readily
on α1 -adrenoceptors in the radial (or dilator) muscle to induce elicited by activation of the hypothalamic defense region in

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cats (134). Recently, cholinergic vasodilation was shown to be fibers. Whether these actions of catecholamines on skeletal
induced in both contracting and non-contracting muscles dur- muscle function are physiologically relevant requires further
ing a voluntary single-leg cycling procedure in humans (141). investigation. However, muscle tremor is a known adverse
The authors concluded that sympathetic vasodilator fibers side effect of β2 -adrenoceptor agonists for the treatment of
contribute to exercise-induced hyperemia. In addition to sym- asthma (258). Likewise, non-selective β-adrenoceptor antag-
pathetic vasodilator systems, a few regions of the circulation onists such as propranolol have been used in the treatment of
receive innervation from parasympathetic nerves to mediate essential tremor (7).
vasodilation; these include the vasculature of the penis and
the cerebral circulation (9, 117).
Autonomic Dysfunction
Regulation of the cerebral circulation is a complex pro-
cess that has attracted a lot of recent interest (80, 117). The Dysregulation of the ANS is the basis or consequence of many
cerebral vasculature is a good example of a target that receives diseases or disorders or a as a result of trauma, the use of some
dual innervation and whose function requires interplay among drugs, or exposure to toxins. Table 8 lists some of these trig-
the ANS, central cholinergic neurons, and local factors. Even gers for autonomic dysfunction, the underlying pathology, and
though anatomical studies showed that nerves supplied the the major autonomic changes encountered. The dysautonomia
cerebral blood vessels over 400 years ago, a functional role can be expressed as either a loss of function (reduction or inac-
for this autonomic innervation is a relatively new concept. tivation of the sympathetic and/or parasympathetic activity;
Rather, cerebral blood flow was thought to be primarily deter- e.g., pure autonomic failure) or a gain in function (excessive
mined by local factors including levels of H+ , adenosine, activation of one or both divisions of the ANS; e.g., neuro-
and K+ that help promote an adequate supply of blood to genic hypertension). The dysfunction can be localized (e.g.,
the brain, independent of neural influences. A powerful neu- Horner’s syndrome) or more generalized (e.g., multiple sys-
rogenic vasodilation follows the co-release of ACh and NO tem atrophy).
from parasympathetic nerve terminals in the cerebral vascu- It is not surprising that there are many similarities in the
lature (117, 168). The source of the parasympathetic inner- autonomic disturbances noted with many of the diseases listed
vation of the cerebral circulation is preganglionic neurons in in Table 8. Not surprisingly, all of the generalized autonomic
the superior salivatory nucleus that project via a branch of neuropathologies have orthostatic or postural hypotension as a
the facial nerve to terminate on postganglionic neurons in the major complication. Several excellent reviews have been writ-
sphenopalatine and otic ganglia (117, 263). Cerebral blood ten on comparing the similarities and differences among mul-
vessels also receive innervation from cholinergic neurons that tiple system atrophy, pure autonomic failure, and Parkinson
are intrinsic to the brain (176). The effects of ACh on the disease (22,105,187). All are examples of chronic autonomic
cerebral circulation are complex and involve M1 , M3 , and failure syndromes and α-synucleinopathies, but the location
M5 cholinergic receptor subtypes. ACh-mediated activation of the inclusion bodies varies from glia (multiple system atro-
of M1 and M3 receptors causes vasoconstriction and vasodi- phy), autonomic ganglia (pure autonomic failure), to central
lation, respectively. The vasoconstriction appears to be due neurons (Parkinson disease). The autonomic impairment is
to ACh-mediated inhibition of NO. The M5 receptors in the predominantly in preganglionic neurons (both sympathetic
cerebral vasculature function in the activation of NOS; in and parasympathetic) in multiple system atrophy and in post-
fact NO is likely the major factor responsible for neurogenic ganglionic neurons in the other two pathologies.
vasodilation in the cerebral circulation (84, 117, 248). Sym- Both familial dysautonomia and dopamine β-hydroxylase
pathetic fibers emanating from the superior cervical ganglion deficiency are examples of dysfunction due to an autosomal
innervate the cerebral circulation; NE is the dominant trans- recessive trait. While the former presents with both sympa-
mitter and acts on α1 -adrenoceptors to mediate constriction thetic and parasympathetic dysfunction, the parasympathetic
in large vessels but causes little or no change in the diameter nervous system is spared in the latter (105, 187, 221). Auto-
of small caliber vessels (117). nomic disturbances can result from inflammatory disorders
such as Guillain-Barre syndrome (42), metabolic diseases
such as diabetic autonomic neuropathy (256), and autoim-
Sympathetic nerves can affect the function of mune disorders such as autoimmune autonomic ganglionopa-
non-autonomic target organs thy (254).
So far when discussing the physiological effects of activation Autonomic dysfunction can be a consequence of the use
of the ANS, the information has been limited to changes in of some drugs that cause nerve damage (e.g., vincristine, cis-
autonomic effector organs. But sympathetic nerve activity can platin, perhexiline maleate, and thallium) due to impaired
also affect the function of skeletal muscles via its influence metabolism or the production of toxic metabolites (186).
on glucose and protein metabolism, ACh release from the α- In addition to the many drugs listed in Table 5 which
motor neurons, ion transport across the cell membrane, and modify neurotransmission in the ANS, changes in sympa-
Ca2+ release and reuptake from the sarcoplasmic reticulum thetic and/or parasympathetic activity occur during the use
(220). These actions are primarily mediated by binding of cir- of many other drugs such as barbiturates and anesthetics
culating epinephrine to β2 -adrenoceptors on skeletal muscle which can reduce sympathetic nerve activity and tranquilizers

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Table 8 Autonomic Dysfunction

Cause Pathology Autonomic profile References

Pure autonomic failure Degeneration of preganglionic neurons; Impotence; orthostatic hypotension and supine (105, 187)
(Bradbury-Eggleston lack of NE uptake and synthesis in hypertension; impaired sweating; nocturia,
syndrome) sympathetic postganglionic neurons; urinary hesitancy, occasional incontinence;
α-synuclein-containing neuronal denervation hypersensitivity of adrenoceptors;
cytoplasmic inclusions (Lewy bodies) in impaired baroreflex
ganglia and peripheral autonomic
nerves
Multiple system α-Synuclein accumulation in glia; Widespread failure of autonomic effector organs; (22, 187)
atrophy/Shy-Drager degeneration of sympathetic and orthostatic hypotension; urinary frequency and
syndrome parasympathetic preganglionic neurons urgency; impotence; heat intolerance, impaired
thermoregulatory sweating; constipation; dry
mouth
Parkinson disease Degeneration of dopamine neurons in Orthostatic intolerance and hypotension; absence (119, 120)
Substania Nigra; sympathetic of respiratory sinus arrhythmia; urinary
denervation, decreased synthesis, frequency, urgency and incontinence; erectile
release, reuptake, and turnover of dysfunction; chronic constipation
cardiac NE
Familial dysautonomia Splicing mutation in IKBKAP gene of the Lack of emotional tears, excessive sweating and (13, 237)
(Riley-Day syndrome) Ashkenazi Jewish population; sensory salivation, transient severe hypertension, delayed
and autonomic dysfunction gastric emptying, gastroesophageal reflux, skin
blotching, postural hypotension, abnormal
baroreflex and chemoreflex responses; both
sympathetic and parasympathetic involvement
Dopamine β-hydroxylase Genetic deficiency leading to inability to Episodic hypothermia, hypoglycemmia, and (221)
deficiency synthesize NE or epinephrine in hypotension in infants; profound orthostatic
sympathetic postganglionic neurons hypotension in childhood
Guillain-Barré syndrome Acute immune-mediated polyneuropathy Sympathetic hyperactivity and parasympathetic (42)
that often follows an antecedent infection hypoactivity; hypertension, postural hypotension,
and tachycardia; urinary retention;
gastrointestinal motility disorders
Autoimmune autonomic Disruption of fast synaptic transmission in Severe orthostatic hypotension; anhidrosis; reduced (254)
ganglionopathy autonomic ganglia due to presence of tearing; dry mouth; dilated and unreactive pupil;
antibodies to the α3 subunit of the constipation; urinary retention
nicotinic cholinergic receptor
Diabetic autonomic Complication of diabetes mellitus; Tachycardia; orthostatic hypotension; gastroparesis, (256)
neuropathy metabolic insult to nerves, neurovascular constipation, diarrhea; neurogenic bladder;
insufficiency, autoimmune damage, erectile dysfunction; anhidrosis, heat intolerance;
neurohormonal growth factor deficiency Argyll-Robertson pupil; hypoglycemia-associated
autonomic failure
Spinal cord injury Loss of descending input to sympathetic Symptoms vary depending on level of disruption; (137)
preganglionic neurons hypotension; persistent bradycardia;
hypothermia; autonomic dysreflexia; impaired
micturition; sexual dysfunction; delayed
gastricemptying, reduced gastric acid secretion,
bowel dysfunction
Horner syndrome Various pathologies that interrupt Classic triad response of miosis, ptosis, and facial (22)
sympathetic nerve to the eye (e.g., anhidrosis
carotid artery dissection, ischemic lesion
of the hypothalamus, tumor, and trauma
to brachial plexus)
Bogorad syndrome Secondary to Bell’s palsy; regenerated “Crocodile tears”; excessive lacrimation while (186)
nerves distributed to lacrimal glands eating
instead of salivary glands
Autonomic-mediated Episodic hypersensitivity of the autonomic Combination of parasympathetic hyperactivity (186)
syncope (vasovagal nervous system; overactive autonomic (bradycardia) and sympathetic withdrawal
syncope, carotid sinus reflexes (hypotension); loss of consciousness
hypersensitivity, situational
syncope)
Complex regional pain Occurs following trauma, ischemia, or Cutaneous vasodilation; either anhidrosis or (229)
syndrome (reflex nerve compression in a limb hyperhidrosis; distal swelling due to increased
sympathetic dystrophy) sympathetic nerve activity

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and antidepressants that can decrease parasympathetic nerve loss of sympathetic nerve activity so the magnitude of the
activity (182, 186). Withdrawal from alcohol, opioids, and fall can inform one about the prevailing level of sympathetic
benzodiazepines cause tachycardia, hyperhidrosis, and hyper- activity. This strategy has been used to determine that an
tension; herbal drugs like ephedra and weight loss drugs such increase in sympathetic nerve activity occurs in several forms
as dexfenfluramine can also induce hypertension (182). The of hypertension (e.g., angiotensin II-induced and salt-induced
use of atypical muscle relaxants (e.g., tizanidine), phospho- hypertension). This conclusion was based on the finding that
diesterase type 5 inhibitors (e.g., sildenafil), and narcotics the ganglionic blockade-induced fall in arterial pressure was
(e.g., opioids, benzodiazepines) has been associated with the greater in the hypertensive model than in the normotensive
development of hypotension (182). control model (159, 267). Indeed, one of the first pharmaco-
Several toxins and toxicants are also known to impair logical approaches to the treatment of hypertension in human
the ANS. In addition to botulinum toxin and mushroom poi- subjects was the use of ganglionic blocking agents like hex-
soning described above (38, 65, 156, 238), autonomic dys- amethonium (76, 250).
function can also occur from exposure to mercury, jellyfish Spectral analysis of beat-to-beat fluctuations in heart rate
and marine animal venoms, organic solvents, and acrylamide and blood pressure variability is a noninvasive approach that
(186). Symptoms can include anhidrosis or hyperhidrosis, provides information about parasympathetic and sympathetic
diarrhea or constipation, urinary incontinence or retention, nerve influences on the heart and or vasculature in healthy
gastroparesis, Sjogren syndrome (dry eyes, dry mouth, and subjects or in those with a known pathology such as heart
connective tissue disease), blurry vision, facial flushes, ortho- failure (201, 218). The two major spectral frequency compo-
static intolerance, or sexual dysfunction. nents commonly considered are those falling in a low fre-
quency (LF) range of approximately 0.04 to 0.15 Hz and a
Indices of Autonomic Nerve Activity high frequency (HF) range of approximately 0.15 to 0.4 Hz.
It is generally accepted that that vagal influences on heart
As described above, autonomic dysfunction is a hallmark of rate occur in the HF range, so changes in the HF band of
various common diseases and disorders. Thus it is not surpris- the power spectrum of heart rate variability reflects changes
ing that investigators have sought ways to characterize how in vagal control of the heart. The HF band is also the fre-
autonomic function is changed either as a cause or an effect of quency range at which respiratory influences on heart rate
these pathologies in various animal and human subject mod- occur; this is called the respiratory sinus arrhythmia. Related
els. This includes the ability to monitor the impact of disease to this, the HF band of the power spectrum of systolic blood
on sympathetic nerve activity. Numerous reviews have been pressure variability may reflect the mechanical effects of res-
written on the assessment of sympathetic or parasympathetic piration on the pressure gradients, size, and function of the
nerve activity using direct and indirect methods in humans and heart and large thoracic vessels (201). There is less agreement
animal models (59, 92, 96, 97, 119, 124, 137, 185, 261, 271). that changes in the LF band of the power spectrum of heart
Some of the commonly used assessments of the ANS are rate or systolic blood pressure variability are reliable indices
based on triggering the activation of cardiovascular reflexes of changes in sympathetic nerve activity. Indeed, many phys-
through altering blood pressure in human subjects. There are iological and psychological manipulations that are known to
numerous protocols that raise blood pressure through sym- increase sympathetic nerve activity do not increase (and, in
pathoexcitatory mechanisms, including mental stress, cold fact, sometimes decrease) LF power in heart rate or systolic
pressor test, and handgrip exercise. In addition, examination blood pressure variability.
of the blood pressure response to various interventions can Measurement of plasma catecholamines and their deriva-
be used to assess sympathetic reactivity and baroreflex sen- tives has been used as a global index of sympathetic ner-
sitivity. These interventions include the Valsalva maneuver, vous system activity in humans and animal models (89, 116,
various orthostatic challenges with active standing and passive 161, 271). In this context, the most commonly assessed cat-
tilt table testing, neck suction/pressure, lower body negative echolamines are NE, epinephrine, DHPG, and DOPAC. It is
pressure, carotid sinus massage, and pharmacological barore- important to be mindful that the measured venous levels of
flex challenges. Finally the parasympathetic nervous system NE are representative not only of the vesicular release of NE
is often examined using tests of cardiovagal function which from sympathetic nerve terminals, but also the effectiveness
include measurement of the heart rate response to deep breath- of junctional clearance by NET (i.e., uptake 1). Investiga-
ing (i.e., respiratory sinus arrhythmia), the mammalian dive tors should be cautious in interpretations of plasma NE levels
response, Valsalva maneuver, and other orthostatic challenges for this reason. In addition, there is not a linear relationship
involving postural change. between sympathetic nerve activity and NE in the plasma;
Some investigators have relied on measurements of the one must also consider the effect of changes in organ/regional
fall in arterial pressure that occurs after either surgical or blood flow that would impact overall NE clearance. Venous
chemical blockade of autonomic ganglia in animal models plasma NE therefore may not provide an accurate index
(159, 267). Since ganglionic blockade disrupts sympatheti- of sympathetic function; however, it is still useful since
cally mediated vasoconstriction, a depressor response that there is a baroreflex-mediated elevation in NE upon standing
results from ganglionic blockade is assumed to reflect the (161) showing that venous NE levels change in response to

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Comprehensive Physiology Overview of the ANS

sympathetic neural challenges. Given these limitations, Esler related to sweating (97). These include the thermoregulatory
and colleagues pioneered the use of radiotracer technology sweat test, quantitative sudomotor axon reflex test (QSART),
to measure NE spillover as an index of regional sympa- skin sympathetic response/skin potentials, the sweat imprint
thetic nerve activity (89). In fact, regional NE spillover is test, and the recently developed quantitative direct and indirect
now viewed as the gold-standard for quantifying changes in reflex test (QDIRT).
sympathetic nerve activity, especially in human subjects. An
intravenous infusion of small amounts of tritiated NE is fol-
lowed by regional venous blood sampling. The spillover is Conclusion
quantified as the arteriovenous difference in NE levels across
This article provides an overview of the major properties of
an organ (after correction for the extraction of arterial NE)
the ANS as a resource for those interested in gaining a better
multiplied by the organ plasma flow. This approach is useful
appreciation of the important role it plays within the broader
for comparing basal levels of regional NE spillover among
field of neuroscience. For example, the definitive experiment
different subjects. However, it can only make measurements
that proved the existence of chemical neurotransmission was
at a single point in time, so is it is not useful for evaluating
a study of the vagal nerve control of the heart rate. Also, the
short term changes in sympathetic nerve activity.
major mechanism of action of many prescription and over-
The most specific measure of sympathetic activity is to
the-counter drugs is to facilitate or attenuate transmission
directly record the electrical activity within a sympathetic
within the ANS or its neuroeffector targets. Dysfunction of
nerve. The first publication showing the recordings from a
the ANS is a cause or result of many neurological disorders.
sympathetic nerve was the work of Adrian and colleagues (5).
Many scientists who worked in the field of the ANS have been
They described bursts of activity in cervical and abdominal
recipients of the Nobel Prize in Physiology or Medicine for
sympathetic nerves of anesthetized cats and rabbits that were
studies that have helped to define integrative physiology.
synchronized to the phases of the cardiac cycle; the ampli-
The ANS has regulatory properties that distinguish it from
tude of these pulse-synchronous bursts waxed and waned on
the somatomotor nervous system. This includes the fact that
the time scale of the respiratory cycle. Beginning soon after
the ANS mediates control over its effector organs via the
this study and continuing through the 21st century, various
use of two distinctive components: the sympathetic nervous
investigators have noted that sympathoexcitatory and sympa-
system and the parasympathetic nervous system which can
thoinhibitory neurons in the brainstem (e.g., rostral ventrolat-
act as physiological antagonists, synergistically, or indepen-
eral medulla, caudal ventrolateral medulla, caudal medullary
dently. Also the ANS establishes a delicate balance between
raphé, lateral tegmental field, caudal ventrolateral pons, and
relaxation and contraction of its neuroeffector targets whereas
rostral dorsolateral pons) contribute to setting the level and
neural control of skeletal muscle is simply via changing the
pattern of ongoing activity in sympathetic nerves [see reviews
degree of contraction.
by Barman and Gebber (16) and Hou and Rabchevsky (137)].
Via its widespread innervation of glands, smooth muscles,
About 36 years after the work of Adrian and colleagues,
and the heart, the ANS is like the conductor of an orchestra as
Karl-Erik Hagbarth was the first to record sympathetic nerve
it coordinates the interplay among cells, tissues, and organs
activity in a conscious human subject (126, 252). He intro-
throughout the body to maintain homeostasis. Of course, the
duced the use of microneurography by inserting a needle into
ANS does not work in isolation from the rest of the body’s reg-
his own ulnar nerve. As was the case for sympathetic activity
ulatory systems. Rather, it works in harmony with behaviors,
in anesthetized cats and rabbits, Hagbarth and Vallbo (126)
emotions, and the immune system and is highly integrated
reported that bursts of muscle sympathetic nerve activity were
with the neuroendocrine system.
synchronized to his heart beat and respiration.
Since these pioneering studies of Adrian et al. (5) and
Hagbarth and Vallbo (126), many investigators have recorded Acknowledgements
the activity from the sympathetic innervation of many tar-
get organs, including the heart, kidney, mesentery, skele- The authors would like to thank James Poteracki for assistance
tal muscle vasculature, and spleen (16, 124, 184, 185). Due during the writing of this article.
to the near uniform appearance of pulse-synchronous and
respiratory-related rhythmic activity in these nerves, they are
now regarded as the hallmark of sympathetic nerve activity References
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