PHYSIOLOGY OF PAIN PATHWAYS

AND WHO PAIN LADDER

MODERATOR-
DR.TEJESWI SAI
PRESENTER- DR.TRIPTI NAGDEV
• PAIN IS THE RESPONSE OF THE MIND TO A NOXIOUS STIMULUS.
• The experience of pain involves a series of complex neurophysiologic
processes , collectively termed “nociception”, with four different
components.
GATE THEORY
ASCENDING AND DESCENDING
PATHWAYS
 ASCENDING PATHWAY
• From the spinal cord to sites in the brainstem and thalamus are important
for perception and integration of nociceptive information .
• The major ascending pathways for pain include the SPINOTHALAMIC
TRACT , SPINOMEDULLARY and SPINOBULBAR PROJECTIONS , and
SPINOHYPOTHALAMIC TRACT.
• Some indirect projections , such as the dorsal column system and the
spinocervicothalamic pathway, also exist to forward nociceptive
information to the forebrain through the brainstem.
• Similar pathways originating from the medulla trigeminal sensory nuclei
also exist to process the nociceptive information from the facial
structures.
 SPINOTHALAMIC TRACT
• STT is the most closely associated with pain , temperature and itch
sensation.
• STT originates in the spinal dorsal horn neurons in lamina I ( receiving
inputs from small diameter A delta and C primary afferent fibres ),
laminae IV and V( receiving input from large diameter A beta fibres from
skin ) and laminae VII and VIII( receiving inputs from skin , muscle and
joints )
• 85 to 90 % of neuronal cells with projection extending through STT are
found on contralateral side , 10-15% on the ipsiateral side .
• The axons of STT cells generally cross in the dorsal and ventral spinal
commissures to reach the white matter of contrlateral spinal cord within
one or two segments rostral to the cells of origin.
• The lateral STT originates predominantly from lamina I cells , and the
anterior STT originates from deeper laminae V and VII cells.
• In the lateral STT, the axons from caudal body regions tend to be located
more laterally , in the white matter , whereas those from rostral body
regions are located more medially .
• Axons from STT terminate in regions of the thalamus.
 SPINOBULBAR TRACT
• Originate from laminae I, V , VII in the spinal dorsal horn. Spinal
projections to the medulla are bilateral, and those to the pons and
mesencephalon have a contralateral dominance.

• Ascending spinobulbar projections terminate mainly in four areas of the

brainstem, including he regions of the catecholamine cell groups (A1 –
A7), the parabrachial nucleus , PAG, and he brainstem reticular formation.

• Spinal projections to the brainstem are important for the integration of

nociceptive activity with processes that subserve homeostasis and
behaviour.
 SPINO HYPOTHALAMIC TRACT
• Originates bilaterally from cells in laminae I, V, VII and X over the entire
length of the spinal cord .

• The SHT axons have connections with the contrlateral diencephalon ,

decussate in the optic chiasm , and then descend ipsilaterally through thr
hypothalamus and as far as the brainstem.

• The SHT appears to be important for autonomic , neuroendocrine , and

emotional aspects of pain.
 SUPRASPINAL MODULATION OF
NOCICEPTION
• The most commonly activated regions during acute and chronic pain
include SI , SII , ACC ( anterior cingulate cortex), insular cortex (IC),
prefrontal cortex , thalamus , and cerebellum
• These brain regions form a cortical and sub cortical network , which are
critically involved in formation of emotional aspects of pain and the
central modulation of pain perception.
• The SI ansd SII receive noxious and innocuos somatosensory input fro
somatosensory thalamus.
• Cingulate cortex receives input from medial thalamic nuclei and lateral
thalamic regions.
• The IC receives direct thalamocortical nociceptive input in the primate.
• The Prefrontal cortex receives input from ACC
• Somatosensory cortices (SI and SII ) are importnt for perception ofsensory
features ( location and intensity of pain )

• Limbic and paralimbic regions (ACC and IC) are more important for
emotional and motivational aspects of pain.
 DESCENDING PATHWAYS OF PAIN
MODULATION
• Originate from supraspinal regions may suppress nociceptive transmission
through dorsal horn , termed Descending inhibition pathway (DI) and
descending facilitation pathway (DF).
• The (Peri aqueductal grey matter )PAG and and the RVM ( rostral
ventromedial medulla ) regions of the brain stem are the critical brain
regions underlying descending pain modulation .
• PAG neurons receives inputs from amygdala , nucleus accumbens ,
hypohalamus and others , with ascending nociceptive afferets from dorsal
horn.
• The PAG and the adjacent nucleus cuneiformis are major source of inputs
to the RVM
• The RVM receives input from serotonin- conataining neurons of dorsal
raphe and neurotensinergic neurons of PAG.
• THE PAG -RVM connection is critical for pain modulation.
• The PAG projects only minimally to the spinal cord dorsal horn, and the
pain-modulating action of the PAG on spinal cord is relayed largely , if not
exclusively , through the RVM.
• Spinally projecting noradrenergic neurons of the pontine tegmentum
conribute significantlly to pain modulation.
• The locus ceruleus and A5 & A7 noradr cell group- MAJOR source of
projections to dorsal horn.
• Electric stimulation in these regions produces behavioral analgesia and
inhibition of dorsal horn neurons mediated by spinal alpha2- adrenergic
receptors.
• Electric stimulation of RVM ,can produce inhibition or facilitation of dorsal
horn nociceptive processing
• 3 distinctive population of neurons in the RVM
1)On cells – those that discharge just prior to occurrence of withdrawal from
noxious heat.
2)Off cells – those that stop firing just prior to a withdrawal reflex
3) Neutral cells – that show no consistent change in activity when withdrawal
reflex occur .
• The On and OFF cells project to laminae I, II and V of dorsal horns .
• Activation of RVM neurons , could inhibit nociceptive transmission in.
dorsal horn via either
- Direct inhibition of projection neurons or
- Activation of inhibitory interneurons in dorsal horn.
• OFF CELLS – exert net inhibitory effect on nociception
• ON CELLS - net facilitatory effect on nociception .
• NEUTRAL CELLS –are serotonergic neurons , and their projections release
serotonin at level of dorsal horn and modulate the action of other
descending pain modulation systems via 5HT3 receptors.
 TRANSITION FROM ACUTE TO
CHRONIC PAIN
• Acute pain is limited to the short – term , typically extending for days to
weeks after injury and provides an important protective mechanism ,
signalling the individual to protect the injured region from repeated injury
, so that tissue healing can ensue.

• As the tissue heals , acute sensitization in the region surrounding the

injury gradually subsides, and sensory threshold revert to normal.

• Acute pain and the accompying sensitization that accompany any injury do
not typically persist after the initial injury has healed.

• In contrast, chronic pain is persistent pain that persists after all tissue
healing appears to be complete and extends beyond expected period of
healing.
• In individuals with chronic pain , pain receptors continue to fire , even in
the absence of tissue damage .
• There may no longer be a physically discernible tissue injury, yet the pain
response persists.
• There is no clear delineation between when acute pain ends and chronic
pain begins .

• While sensitization of peripheral and central nocisponsive neurons

underlies the neurobiologic basis of the transition from acute to chronic
pain, emerging evidence also suggests that an individual’s psychologic
response after injury as well as noxious stimuli induced epigenetic
modification in the CNS & PNS are also involved in the induction &
maintenance of chronic pain.
 PSYCHOBIOLOGY OF PAIN
• Unpleasant emotional experiences are an intrinsic and undesirable
feature of painful experiences for the patients.
• Discomfort , fear of pain , and anxiety are most common psychological
responses observed in patients with pain, although other adverse
emotional responses, including depression, anger , disgust and guilt are
not unusual in these patients.
• “Affective Qualities “ of pain are transmitted and processed via the same
pathways as for sensory transmission.
• Peripheral nociceptive information is delivered through spinoreticular
pathways to diencephalon and telencephalon, including the medial
thalamus , hypothalamus, amygdala and limbic cortex.
• Centrl sensitization and adaptation of synaptic plasticity occur in these
brain regions and contribute to induction and maintenance of emotional
distress that accompanies pain.
• Intrinsic interactions occur between sensory and affective components of
pain.
• While these affective symptoms may gradually wane , a susbstantial
proportion of patients with chronic pain experience dleibitating
depression , anxiety , cognitive deficits such as memory impairment and
other negative psychological components of pain.
• Severe emotionl distress can trigger new pain or exacerbate ongoin pain in
patients with previous painful experiences.
 SOME SPECIFIC TYPES OF PAIN
• NEUROPATHIC PAIN
• Neuropathic pain is pain that persists after tissue injury has healed and is
characterized by reduced sensory and nociceptive thresholds(allodynia
and hyperalgesia )
• Injury of peripheral nerves by trauma , surgery or diseases(eg diabetes )
frequently results in development of neuropathic pain.
• Cancer patient are increased risk of neuropathic pain caused by
chemotherapy and radiotherapy .
• Neuropathic pain actually reflects a maladaptive(pathophysiologic )
function of a damaged pain system.
• Persists throughout life and negatively affects physical , emotional and
social quality of life.
• Pathophysiologic process that leads to neuropathic pain has hallmarks of
neuroinflammatory response following innate immune system activation.
• TLR2 and TLR4 found on microglia appear to trigger glial activation ,
initiating proinflammatory and signal transduction pathways that lead to
the production of proinflammatory cytokines.
• Central cannaboid receptor type 2 (CB2) plays a protective and
administration of CB2 receptor agonist can blunt the neuroinflammatory
response and prevent peripheral neuropathy through interference with
signalling pathways.
• The pathologic feature of neural damage include segmental abnormal
myelination/de myelination axonopathy, ranging from metabolic and
axoplasmic transport deficits to frank transection of the axon(axotomy).
• After nerve injury , proximal stump seals off forming and “end bulb” and
numerous fine processes “sprouts” start to grow from bulbs after 1-2 days.
• They elongate within their original endoneurial tube and restore the
normal sensation in appropriate periphral targets.
• However , when the forward growth of axon is blocked, eg after limb
amputation, end bulbs and aborted sprouts form a tangled mass “nerve
end neuroma”
• The ectopic firing , generated in end bulb and sprouts within the neuroma
, as well as cell bodies in DRG, significantly contribute to nociceptive
hypersensitivty and ectopic mechosensitivity that follow nerve injury.
• VISCERAL PAIN
• Is diffuse and poorly localised, typically referred to somatic sites (eg
muscles and skin ) and it is usually associated with stronger emotional and
autonomic reactions .
• Is produced by stimuli differentfrom those for activation of somatic
nociceptors.
• These features may be attributable to dual nerve innervation and the
unique structure of visceral receptive endings.
 COMPLEX REGIONAL PAIN
SYNDROMES
• The International Association for the study of pain (IASP) classification of
chronic pain defines complex regional pain syndrome (CRPS) as “ variety of
painful conditions following injury which appears regionally having a distal
predominance of abnormal findings , exceeding both magnitude and
duration the expected clinical course of the inciting event often resulting
in significant impairment of motor function , and showing variable
progression over time. “

• These chronic pain syndromes have different clinical features including

spontaneous pain , allodynia , hyperalgesia, edema, autonomic
abnormalities, active and passive movement disorders , and trophic
changes of skin and subcutaneous tissues.
• Two types of CRPS ;
• Type I (reflex sympathic dystrophy )
• Type II (causalgia ) presence of major identifiable nerve injury in CRPS .
• CRPS type I more common.
• Females are more common.
• The incidence of CRPS I is 1 to 2 % after fractures ,12% after brain lesions ,
5% after myoxardial infarction
• CRPS II in peripheral nerve injury varies from 2 to 14 %
• The mechanism underlying pathoigenesis of CRPS remains unclear ,
although it is recognised that CRPSis a neurologic disease inclujding the
autonomic, sensory and motor systems as well as cortical areas involved in
processing of cognitive and affcetive information, and the inflammatory
component appears to be impotant inn acute phase of disease.
WHO PAIN LADDER
ACTION SITE OF VARIOUS DRUGS