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Pleasure-Seeking Behaviour
Pleasure and Drugs
Avoiding Pain

HelpLink : The Painful History of Substance PLink : Pain ReceptorsLink : Substance P
Link : Pain and neurotransmittersLink : Six Easier Pieces

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 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.


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 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 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.

Link : Hot Chili Peppers Help Unravel The Mechanism Of PainLink : Capsaïcine, receptors vanilloïdes, VR, TRPVLink : Les receptors vanilloïdes et leurs ligandsLink : Vanilloid (Capsaicin) Receptors and MechanismsExperiment : Depletion of substance P and glutamate by capsaicin blocks respiratory rhythm in neonatal rat in vitro



Link : Columbia University Researchers Discover On-off Switch For Chronic PainLink : Researchers show how the brain can protect against cancerLink : MorphineLink : Opium
Link : DynorphinLink : ENKEPHALINESLink : Dynorphin, Analogs and SequencesLink : Opioid peptides
Link : The Endomorphin System and Its Evolving Neurophysiological RoleLink : Endomorphins
Experiment : Isolation, primary structure, and synthesis of ?-endorphin and ?-endorphin, two peptides of hypothalamic-hypophysial origin with morphinomimetic activityExperiment : Reverse physiology: discovery of the novel neuropeptide, orphanin FQ/nociceptinExperiment : Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor
History : As Morphine Turns 200, Drug That Blocks
Original modules
Tool module : Anaesthesia and AnalgesiaAnaesthesia 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.

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 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 sialorphin could also help researchers to design new medications that could reduce pain by preventing the breakdown of endogenous opioids.

Researcher : Le parcours remarquable de Catherine RougeotLink : La découverte de l'opiorphine humaine : un modulateur anti-nociceptif des voies opioïdergiques

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.

Opium smokers in France, cover of Le Petit Journal, July 5, 1903

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.”

The complex molecular structure of morphine was first described many years later, in 1925, 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-enkephalinare 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.

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.

Enkephalins are secreted in all the structures of the central and peripheral nervous systems, close to the 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.

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 B, and alpha and beta neoendorphin. These four peptides contain the exact same sequence of amino acids as leu-enkephalin, but with additional amino acid molecules as well (12, 8, 5, and 4, respectively).

Dynorphin A
(Source: JaGa)

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
a-Neoendorphin: Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys
b-Neoendorphin: Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro

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.


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 causes the skin to darken in response to the sun’s rays.

Summary of the possible derivatives of POMC

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.

Endomorphin 1

Endomorphin 1: Tyr-Pro-Trp-Phe-NH2

Endomorphin 2: Tyr-Pro-Phe-Phe-NH2

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 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.

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 effects of other opioid peptides).

Orphanin FQ/nociceptin
Source: Edgar181

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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