Endorphin.

Endorphins are endogenous opioid polypeptide compounds. They are produced by the
pituitary gland and the hypothalamus in vertebrates during strenuous exercise,[1]
excitement, pain, and orgasm,[2]HYPERLINK \l "cite_note-
urlGet_more_than_zeds_in_bed_-_Mind_.26_body_magazine_-_NHS_Direct-2"[3] and
they resemble the opiates in their abilities to produce analgesia and a sense of well-being.
Endorphins work as "natural fever relievers", whose effects may be enhanced by other
medications.
The term "endorphin" implies a pharmacological activity (analogous to the activity of the
corticosteroid category of biochemicals) as opposed to a specific chemical formulation. It
consists of two parts: endo- and -orphin; these are short forms of the words endogenous
and morphine, intended to mean "a morphine like substance originating from within the
body."[4]
The term endorphin rush has been adopted in popular speech to refer to feelings of
exhilaration brought on by pain, danger, or other forms of stress,[1] supposedly due to the
influence of endorphins. When a nerve impulse reaches the spinal cord, endorphins are
released which prevent nerve cells from releasing more pain signals. Endorphins allow
someone to immediately after injury feel a sense of power and control over themselves
which allows them to persist with activity for an extended time.

History
Opioid neuropeptides were first discovered in 1975 by two independent groups of
investigators.

• John Hughes and Hans Kosterlitz of Scotland isolated — from the brain of a pig
— what they called enkephalins (from the Greek εγκέφαλος,
cerebrum).[5]HYPERLINK \l "cite_note-5"[6]

• Around the same time in the calf brain, Rabi Simantov and Solomon H. Snyder of
the United States found[7] what Eric Simon (who independently discovered
opioid receptors in the brain) later termed "endorphin" by an abbreviation of
"endogenous morphine", which literally means "morphine produced naturally in
the body".[citation needed] Importantly, recent studies have demonstrated that
diverse animal and human tissues are in fact capable of producing morphine itself,
which is not a peptide.[8]HYPERLINK \l "cite_note-pmid17006413-8"[9]
Mechanism of action
Beta-endorphin is released into the blood (from the pituitary gland) and into the spinal
cord and brain from hypothalamic neurons. The beta-endorphin that is released into the
blood cannot enter the brain in large quantities because of the blood-brain barrier. The
physiological importance of the beta-endorphin that can be measured in the blood is far
from clear: beta-endorphin is a cleavage product of pro-opiomelanocortin (POMC) which
is also the precursor hormone for adrenocorticotrophic hormone (ACTH). The
behavioural effects of beta-endorphin are exerted by its actions in the brain and spinal
cord, and probably the hypothalamic neurons are the major source of beta-endorphin at
these sites. In situations where the level of ACTH is increased (e.g. Addison disease), the
level of endorphins also increases slightly.
Beta-endorphin has the highest affinity for the μ1-opioid receptor, slightly lower affinity
for the μ2- and δ-opioid receptors and low affinity for the κ1-opioid receptors. μ-
receptors are the main receptor through which morphine acts. Classically, μ-receptors are
presynaptic, and inhibit neurotransmitter release; through this mechanism, they inhibit the
release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways,
causing more dopamine to be released. By hijacking this process, exogenous opioids
cause inappropriate dopamine release, and lead to aberrant synaptic plasticity, which
causes addiction. Opioid receptors have many other and more important roles in the brain
and periphery however, modulating pain, cardiac, gastric and vascular function as well as
possibly panic and satiation, and receptors are often found at postsynaptic locations as
well as presynaptically.

Activity
Scientists debate whether specific activities release measurable levels of endorphins.
Much of the current data comes from animal models which may not be relevant to
humans. The studies that do involve humans often measure endorphin plasma levels,
which do not necessarily correlate with levels in the CNS. Other studies use a blanket
opioid antagonist (usually naloxone) to indirectly measure the release of endorphins by
observing the changes that occur when any endorphin activity that might be present is
blocked.
Capsaicin (the active chemical in red chili peppers) also has been shown to stimulate
endorphin release.[10] Topical capsaicin has been used as a treatment for certain types of
chronic pain.
Runner's high
Another widely publicized effect of endorphin production is the so-called "runner's
high", which is said to occur when strenuous exercise takes a person over a threshold that
activates endorphin production. Endorphins are released during long, continuous
workouts, when the level of intensity is between moderate and high, and breathing is
difficult. This also corresponds with the time that muscles use up their stored glycogen.
Workouts that are most likely to produce endorphins include, boxing, running,
swimming, cross-country skiing, long distance rowing, cycling, hockey, tennis, weight
lifting, aerobics, or playing a sport such as soccer, basketball, rugby, lacrosse, Paintball
or American football.
However, some scientists question the mechanisms at work, their research possibly
demonstrating the high comes from completing a challenge rather than as a result of
exertion.[11] Studies in the early 1980s cast doubt on the relationship between
endorphins and the runner's high for several reasons:

• The first was that when an antagonist (pharmacological agent that blocks the
action for the substance under study) was infused (e.g. naloxone) or ingested
(naltrexone) the same changes in mood state occurred as when the person
exercised with no blocker.
A study in 2003 by Georgia Tech found that runner's high might be caused by the release
of another naturally produced chemical, Anandamide. Anandamide is similar to the
active endocannabinoid anandamide,[12]HYPERLINK \l "cite_note-pmid14625449-
12"[13] The authors suggest that the body produces this chemical to deal with prolonged
stress and pain from strenuous exercise, similar to the original theory involving
endorphins. However, the release of anandamide was not reported with the cognitive
effects of the runner’s high; this suggests that anandamide release may not be
significantly related to runner's high.[13]
In 2008, researchers in Germany reported that the myth of the runner's high was not a
myth but was in fact true. Using PET scans combined with recently available chemicals
that reveal endorphins in the brain, they were able to compare runners’ brains before and
after a run.[14] The runners the researchers recruited were told that the opioid receptors
in their brains were being studied, and did not realize that their endorphin levels were
being studied in regard to the runner's high.
The participants were scanned and received psychological tests before and after a two-
hour run. Data received from the study showed endorphins were produced during the
exercise and were attaching themselves to areas of the brain associated with emotions
(limbic and prefrontal areas).[15]
An investigated possiblity is that a molecule, such as anandamide carries endorphins
through the blood-brain barrier, as endorphins are too large to cross the BBB by
themselves. If not, endorphins may be produced in the brain itself.
Acupuncture
In 1999, clinical researchers reported that inserting acupuncture needles into specific
body points triggers the production of endorphins.[16]HYPERLINK \l "cite_note-
pmid18803495-16"[17] In another study, higher levels of endorphins were found in
cerebrospinal fluid after patients underwent acupuncture.[18] In addition, naloxone
appeared to block acupuncture’s pain-relieving effects. However, skeptics say that not all
studies point to that conclusion,[19] and that in a trial of chronic pain patients, endorphins
did not produce long-lasting relief. Endorphins may be released during low levels of pain
and physical stimulation when it lasts over 30 minutes. Questions remain as to whether
the prolonged low level of pain stimulation as in Capsaicin, acupuncture and running or
physical activity alone are the threshold that activates endorphin release.
Definition of Endorphin
Endorphin: One of the body's own painkillers, an opioid (morphine-like) chemical produced by
the body that serves to suppress pain.
Endorphins are manufactured in the brain, spinal cord, and many other parts of the body. They
are released in response to neurotransmitters and bind to certain neuron receptors (the same ones
that bind opiate medicines). Endorphins act as analgesics (diminishing the perception of pain)
and as sedatives.
Chemically, endorphins are peptides (amino acid chains that are shorter than proteins) and they
are rapidly inactivated by enzymes called peptidases.

IntroductionPreparations of the opium poppy papaver somniferum have been used for many
hundreds of years to relieve pain. In 1803, Sertürner isolated a crystalline sample of the main constituent
alkaloid, morphine, which was later shown to be almost entirely responsible for the analgesic activity of
crude opium. The rigid structural and stereochemical requirements essential for the analgesic actions of
morphine and related opioids led to the theory that they produce their effects by interacting with a specific
receptor.1 The concept that there is more than one type of opioid receptor arose to explain the dual
actions of the synthetic opioid nalorphine, which antagonises the analgesic effect of morphine in man but
also acts as an analgesic in its own right. Martin (1967) concluded that the analgesic action of nalorphine
is mediated by a receptor, later called the -opioid receptor, that is different from the morphine receptor.2
Evidence for multiple receptors, ,  and , came from the demonstration of different profiles of
pharmacological activity in the chronic spinal dog with the prototype agonists morphine, ketazocine and
N-allylnormetazocine (SKF 10047).3 The existence of the -receptor was subsequently proposed to
explain the profile of activity in vitro of the enkephalins (the first endogenous opioid peptides), and on the
basis of the relative potency of the non-selective opioid antagonist naloxone to reverse endogenous
opioid peptide inhibition of the nerve-evoked contractions of the mouse vas deferens.4 Its existence was
further confirmed by radioligand binding studies using rat brain homogenates.

It is now clear from work carried out in many laboratories over the last 20 years that there are 3 well-
defined or "classical" types of opioid receptor µ,  and  . Genes encoding for these receptors have been
cloned.5, 6, 7, 8 More recently, cDNA encoding an "orphan" receptor was identified which has a high degree
of homology to the "classical" opioid receptors; on structural grounds this receptor is an opioid receptor
and has been named ORL1 (opioid receptor-like).9 As would be predicted from their known abilities to
couple through pertussis toxin-sensitive G-proteins, all of the cloned opioid receptors possess the same
general structure of an extracellular N-terminal region, seven transmembrane domains and intracellular
C-terminal tail structure. There is pharmacological evidence for subtypes of each receptor and other
types of novel, less well-characterised opioid receptors, , , , , have also been postulated. The -
receptor, however, is no longer regarded as an opioid receptor.

Receptor Subtypes

-Receptor subtypes
The MOR-1 gene, encoding for one form of the -receptor, shows approximately 50-70% homology to the
genes encoding for the -(DOR-1), -(KOR-1) and orphan (ORL1) receptors. Two splice variants of the
MOR-1 gene have been cloned, differing only in the presence or absence of 8 amino acids in the C-
terminal tail. The splice variants exhibit differences in their rate of onset and recovery from agonist-
induced internalization but their pharmacology does not appear to differ in ligand binding assays.10
Furthermore, in the MOR-1 knockout mouse, morphine does not induce antinociception demonstrating
that at least in this species morphine’s analgesia is not mediated through - or -receptors.11 Similarly
morphine did not exhibit positive reinforcing properties or an ability to induce physical dependence in the
absence of the MOR-1 gene.