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MOLECULES THAT PRODUCE PAIN
Pleasure-Seeking
Behaviour
Pleasure and Drugs
Avoiding Pain
The steps that lead to the
activation of a nociceptor
are the same as those
for specialized tactile
receptors. The energy of
the pain stimulus, which
may be mechanical,
thermal, or chemical,
alters the conformation of
certain proteins in the
cell membranes of the
A delta or C fibres .
This change in
conformation modifies
the permeability of the
membrane so as to
induce a local excitation
proportional to the
energy of the stimulus.
Once this excitation
reaches a certain
threshold, a nerve
impulse, or action
potential, is transmitted.
And because the
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When a nociceptor fibre detects a pain stimulus on the skin or in an internal organ, the pain
signal is transmitted to the spinal cord and then on to the brain by neural pathways different
from those for the sense of touch.
At each of the synapses along this pain pathway, several neurotransmitters are involved in
carrying the nociceptive message. Those identified to date fall into two major groups:
“classical” neurotransmitters and neuropeptides.
Examples of classical neurotransmitters include glutamate, aspartate, and serotonin. At
least 20 neuropeptides involved in transmitting pain impulses have been identified, including
substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, somatostatin,
cholecystokinin, and ACTH, not to mention the enkephalins, a large family of peptides that
exert an inhibitory effect on the descending control pathways.
A single nociceptive fibre can contain a variety of different peptides and classical
neurotransmitters, and their respective roles remain largely undetermined. It is also hard to
establish any correlations between the kinds of peptides that the various nociceptive
pathways contain and their electrophysiological properties.
It is known, however,
that glutamate and
substance P (a peptide
containing 11 amino
acids and belonging to
the tachykinin family)
seem to be among the
substances most
involved in the
transmission of pain. For
example, substance P
binds to specific
receptors, called NK1
receptors, that are
located on the
nociceptive neurons of
the dorsal horn of the
spinal cord.
Substance P also occurs in the brain, where it is associated with regulation of mood
disorders, anxiety, reinforcement, neurogenesis, neurotoxicity, respiratory rate, nausea, and,
of course, pain. Also, through a phenomenon known as the axon reflex, substance P can be
released in the peripheral nervous system at the site of a tissue injury, where it causes
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 amplitude of an action
potential is always the
same, the variations in
the intensity of the
nociceptive stimulus will
then be translated into
the frequency of the train
of nerve impulses, which
is the neurons’ preferred
method of
communicating with one
another.
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strong vasodilation that can induce the release of various substances, such as bradykinin,
histamine, and serotonin.
In general, substance P has been associated with relatively slow excitatory connections,
and hence with the persistent, chronic pain sensations transmitted by C fibres, whereas
glutamate is involved in the rapid neurotransmission of acute pain associated with A delta
fibres. The receptors for substance P and glutamate can be distributed in different
populations of neurons that preserve their own specific characteristics. But the two types of
receptors can also coexist on the same neurons, as has been observed in several different
parts of the central nervous system. Many pharmaceutical companies have tried to develop
substance P antagonists in hope of using them as powerful analgesics, but the results have
been very disappointing.
In the peripheral nervous system, other substances also contribute to the transmission of
pain and make the nociceptors more sensitive. Some of these substances, such as
hydrogen and potassium ions, arise from the tissue injury itself. Others, such as
leucotrienes and prostaglandins, are associated with the process of inflammation and act by
sensitizing the nociceptors to the substances generated by the injury. Still other substances,
such as substance P, are released by the nociceptors themselves and activate them
directly.
In parallel with the process of descending control of pain and the endorphins associated
with it, which let you tolerate painful bodily effort and focus on something other than pain,
these processes of sensitization and inflammation tend to make you immobilize the injured
part of your body so as to facilitate the effects of this “inflammatory soup” of molecules,
along with the healing process. The increased pain that even the simplest tactile stimuli
produce around the sensitized site of the injury provide a good incentive for you to take
good care of the injured part of your body.
The central sensitization that occurs in the spinal cord can amplify the pain response to a
normal stimulus even further. This sensitization occurs through a different set of cellular
mechanisms.
Nearly a third of the world’s people consume hot peppers such as jalapeños every day. The
“heat” in these peppers comes mainly from capsaicin, a molecule that causes a burning
sensation by binding to special receptors called TRPV1 receptors, located on the
nociceptors. TRPV1 receptors can also be activated by heat or by an endogenous compound,
anandamide, which also activates the brain’s receptors for cannabinoids. Heat and and
anandamide are therefore probably the natural activators of these TRPV1 receptors which, by
chance, can also be activated by an exogenous molecule from a plant, such as capsaicin.
Adapted from: Neuroscience, by Dale Purves et al.
TRPV1 is a member of the vanilloid family of receptors. Vanilloids are channel receptors
that, when stimulated, allow calcium and sodium ions to enter the neuron. As a result, the
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Anaesthesia and
Analgesia
Phylogenetic studies
have shown the
importance of the
endorphins that are
present in all vertebrates.
Some scientists even
believe that these
endorphins may have
helped vertebrates free
themselves from the
automatic protective
reactions otherwise
triggered by nociceptive
stimuli, and thus helped
to encourage behaviours
that are more adaptive in
many situations.
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neuron becomes depolarized, and if the depolarization passes a certain threshold, it triggers
action potentials. The nociceptor then releases substance P, which excites the next neuron
in the ascending nociceptive pathway, and so on up to the brain, at which point you realize
just how spicy that food you’re eating actually is!
And yet, a few seconds later, you often find that it’s not really so spicy as you thought at first.
The reason is that prolonged contact between capsaicin and its receptors desensitizes them.
Ironically, capsaicin can therefore also produce analgesia, caused in part by the depletion of
substance P. That is why capsaicin is one of the main ingredients in certain analgesic and
anti-inflammatory creams that are used to relieve not only simple muscle and joint pain, but
also other forms of pain that are harder to treat, such as arthritis and neuropathic pain.
These creams often contain another ingredient such as lidocaine to reduce the burning
sensation that the capsaicin initially causes.
Capsaicin receptors are found in all mammals, but not in birds, which has enabled
manufacturers to produce squirrel-proof seed for bird feeders! Research has also shown that
mice in which the gene for the capsaicin receptor has been deactivated can drink a capsaicin
solution as if it were ordinary water.
MOLECULES THAT REDUCE PAIN
For millennia, humans have been using
extracts from plants to ease pain and to
achieve altered states of consciousness.
The best known of these plants is probably
the opium poppy.
Opium was most likely known as far back as the time of the Sumerians (about 3 000
B.C.E.), to judge from written records on their cuneiform tablets. Certain Egyptian
documents from the reign of Ramses II (1 300 B.C.E.) explicitly praise this plant’s abilities to
induce sleep and ease pain.
But it was not until the 18th century that opium
became a subject of scientific interest. A first active
ingredient of opium was described as a plant alkaloid
by F. W. Serturner in works published in 1805-1806
and 1817. Because of this substance’s ability to
induce sleep in human beings, Serturner named it
morphium (in English, morphine), after Morpheus,
the god of dreams in ancient Greece.
Not long afterward, Karl Marx made his famous
reference to this plant, when he said that “Religion is
the opiate of the people.”
Opium smokers in France, cover of Le Petit
Journal, July 5, 1903
The complex molecular structure of morphine was first described many years later, in 1925,
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 For example, if a
wounded prey animal
stopped to lick its
wounds instead of
continuing to run from its
predator despite the
pain, its chances of
survival would be limited.
But instead, the
endorphins that the
animal secretes in
response to its fear,
stress, and the physical
exertion of running make
this pain bearable
enough for the animal to
continue to flee.
Thus the endorphins let
the animal give priority to
surviving, and take care
of recovering and healing
later on.
Endorphins help to
explain not only familiar
phenomena such as the
tolerance for pain
displayed by athletes in
the heat of competition
and soldiers in the heat
of combat, but also
another, more mysterious
phenomenon: the
placebo effect.
Experiments conducted
by Jonathan Levine in
1978 showed that some
psychological
suggestions could in fact
trigger the secretion of
endorphins that reduced
the perception of pain.
Subsequent studies,
however, have made the
picture more complex. It
now seems that the
placebo effect has one
component that is
attributable to endorphins
and another that is not.
The former is more
associated with
expectations and the
latter with conditioning.
Once endorphins have
bound to their receptors
and produced their
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by British chemist Robert Robinson. Starting in 1952, scientists were able to chemically
synthesize morphine and its derivatives, eventually also producing compounds whose
structure was similar to morphine but whose effects differed somewhat (for example,
dextromethorphan, an analgesic similar to codeine). After that, opiates very soon became
widely used in medicine. For example, Henri Laborit developed an injectable “cocktail” of
opiates and tranquilizers that was used to facilitate the transfer of wounded soldiers to
operating rooms during the French war in Indochina.
In the 1970s, the discovery of specific receptors for opioids, and then of enkephalins (the
first known “endogenous morphines”) opened new avenues for understanding pain and the
mechanisms by which it is controlled—not only by molecules from outside the body
(medications), but also by molecules that are endogenous, that is, produced by the body’s
own neurons. Research into these endogenous opiates also began to reveal the
mechanisms by which psychological factors such as the placebo effect can alter our
perception of pain.
Chemically, the body’s endogenous opiates are peptides—small proteins that consist of
short chains of amino acids and that are synthesized right inside the nerve cells by means
of the cells’ messenger RNA and ribosomes, just like any other proteins. (More specifically,
all of these peptides are produced by the cleavage of longer, “precursor” proteins.) These
peptides are then carried down the axons to the nerve endings, where they are released.
The general term for these endogenous peptides is “endorphins”, a reference to the
similarity between their effects and those of morphine. At least 20 different endorphins are
known to be present in the human brain. The following paragraphs describe the main
categories of endorphins and the precursor proteins from which they are derived.
Enkephalins—more specifically,
met-enkephalin and leu-enkephalin
—are the first two endorphins to
have been identified. Both of these
peptides consist of a chain of five
amino acids, the first four of which
are identical. The two differ only in
the last amino acid in the chain:
methionine, in the case of met-
enkephalin, and leucine, in the case
of leu-enkephalin.
Met-enkephalin: Tyr-Gly-Gly-Phe-Met
Leu-enkephalin: Tyr-Gly-Gly-Phe-Leu
Enkephalins are produced by the cleavage of a precursor protein called proenkephalin.
Every proenkephalin molecule contains at least seven active peptide molecules, including
four met-enkephalin molecules and one leu-enkephalin molecule. Once the proenkephalin
molecules have been cleaved by what are known as maturation enzymes, these enkephalin
molecules are released.
Enkephalins are
secreted in all the
structures of the central
and peripheral nervous
systems, close to the
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 effects, they are quickly
deactivated. The main
mechanism by which this
deactivation takes place
is that of a family of
enzymes called
peptidases, which break
the endorphins down by
severing the bonds
between the various
amino acids of which
these opioid peptides are
composed.
In 2003, researchers
isolated a substance
called sialorphin that is
secreted in rats.
Sialorphin binds to the
enzymes that would
otherwise break down
enkephalins and thereby
prevents these enzymes
from doing so. The
enkephalins can then
remain active longer,
resulting in a powerful
pain-suppressing effect.
When researchers
injected rats with
sialorphin, they were
able to walk freely over a
bed of nails.
Under natural conditions,
sialorphin is released into
the rat’s bloodstream in
response to stress. For
example, when male rats
are subjected to
conditions of
competition and
aggression among
themselves, sialorphin
reduces the pain that
they feel from the
resulting injuries.
These interesting
properties of rat
sialorphin led
researchers to start
looking for its functional
analogue in humans.
And within a few years,
an equivalent molecule,
opiorphin, was
discovered. Scientists
are now working to
determine in what
situations opiorphin is
secreted in humans and
how it contributes to the
analgesic effect of
endorphins.
A better knowledge of
natural peptidase
blockers such as
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mu and/or delta opioid
receptors that are their
natural receptors.
Shortly after they have
done their job of
modulating pain, these
natural opioids are
deactivated when they
are cleaved by a family
of enzymes known as
metallopeptidases.
A comparison of the structures of an endogenous opiate and morphine shows that
the two molecules have one area that is similar. This explains why they share an
affinity for the opioid receptors in the brain.
Dynorphins are a class of
endogenous opioids that play a
powerful role in modulating
pain. (Their power is reflected in
their name, which, like the word
“dynamic”, comes from the
Greek dynamis.)
Dynorphins are derived from the
precursor protein prodynorphin.
When prodynorphin is cleaved
by the enzyme proprotein
convertase 2 (PC2), several
active opioid peptides are
released, including dynorphin A,
Dynorphin A
dynorphin B, and alpha and (Source: JaGa)
beta neoendorphin. These four
peptides contain the exact same Dynorphin A (1-13) : Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys
Dynorphin B: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr
sequence of amino acids as leu-
a-Neoendorphin: Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys
enkephalin, but with additional b-Neoendorphin: Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro
amino acid molecules as well
(12, 8, 5, and 4, respectively).
Dynorphins are distributed broadly in the central nervous system, but are found in especially
high concentrations in the hypothalamus, the brainstem, and the spinal cord. Their
physiological effects differ with the site where they are produced, and they bind mainly to
kappa opioid receptors (though they also have a strong affinity for mu and delta receptors).
The term endorphin refers not only to endogenous opioid peptides in general, but also to a
specific group of such peptides in particular. These endorphins are distinguished by a Greek
letter at the start of their name. The most important of these is beta-endorphin, which, in
addition to reducing pain substantially (its analgesic power is several times greater than that
of morphine), is also the opioid peptide that produces the greatest sensation of euphoria.
Beta-endorphin is produced in large amounts during sustained physical exercise and
produces this sensation by binding to mu opioid receptors.
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 sialorphin could also help
researchers to design
new medications that
could reduce pain by
preventing the
breakdown of
endogenous opioids.

Beta-endorphin

Beta-endorphin: Tyr Gly Gly Phe Met Thr Ser Glu Lys Ser Gln Thr Pro Leu Val Thr Leu Phe Lys Asn Ala Ile Ile Lys Asn
Ala Tyr Lys Lys Gly Glu

The precursor of beta-endorphin, pro-opiomelanocortin (POMC), is unusual in that its

cleavage yields not only beta-endorphin and other opioid peptides, but also several other
peptide hormones. Depending on the type of tissue where the gene for POMC is expressed,
it will be cleaved differently and produce different peptides.

Thus, in the anterior pituitary

gland, POMC yields not only
beta-endorphin and beta-
lipotropin (an opioid peptide
associated with fat metabolism)
but also adrenocorticotropic
hormone (ACTH), a hormone
secreted in response to stress.
But when the gene for POMC is
expressed in the melanocytes of
the skin, POMC instead yields
the hormone melanotropin,
which triggers the synthesis of
the pigment melanin, which
Summary of the possible derivatives of POMC
causes the skin to darken in
response to the sun’s rays.

POMC, which is also found in the hypothalamus, is a chain of 241 amino acids and can be
split at various points by enzymes called prohormone convertases. One of its derivatives,
beta-lipotropin, has 90 amino acids and was first isolated in 1964 by biochemist C. H. Li.
Initially, Li could not determine what its function might be, but after seven years he
discovered that beta-lipotropin was, among other things, a precursor of beta-endorphin.
Beta-endorphin comprises 31 amino acids, making it the longest member of its family, which
also includes alpha-, gamma-, and sigma- endorphin.

The neurons of the hypothalamus also

contain another group of opioid peptides
discovered in the late 1990s: endomorphin 1
and endomorphin 2, two small peptides that
have four amino acids and the greatest
known affinity with the mu opioid receptors.

The name endomorphin (not endorphin, as in

Endomorphin 1
Endomorphin 1: Tyr-Pro-Trp-Phe-NH2
Endomorphin 2: Tyr-Pro-Phe-Phe-NH2
beta-endorphin) is a reminder that these
proteins are produced naturally within our
own bodies and bind to the same receptors
that enable exogenous substances such as
morphine to produce their effects.

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 The anatomical distribution of endorphins in the body suggests that they play a role in pain
control, responses to stress, wakefulness, and the reward circuit.

Also in the late 1990s,

another opioid peptide was
discovered: orphanin FQ (or
nociceptin), which has 17
amino acids, is derived from
the precursor
prepronociceptin, and binds
to only a very limited extent
to classic opioid receptors.
Instead it prefers an atypical
class of opioid receptors
called orphan receptors
(whence its name).

The mechanism by which

orphanin is involved in the
perception of pain is
complex, because it can act
as an analgesic at some
times and an anti-analgesic
at others (by blocking the Orphanin FQ/nociceptin
Source: Edgar181
effects of other opioid
peptides). Orphanin FQ/nociceptin: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-
Lys-Leu-Ala-Asp-Glu

One last opioid peptide that should be mentioned here is nocistatin, which also is derived
from the precursor prepronociceptin and is apparently involved not only in the transmission
of pain, but also in memory and learning.

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