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Pleasure and pain

Pleasure-Seeking Behaviour

Pleasure and Drugs

Avoiding Pain

The surface of the body—the skin—contains very large numbers of the free nerve endings known as nociceptors, which is why it is so sensitive to pain. These nociceptors are located both in the epidermis (the surface layer of the skin) and the dermis (the deep layer) and are concentrated in the parts of the body that are the most exposed to injuries, such as the fingers and toes. That is why it hurts more to get a piece of glass stuck in your finger or toe than in, say, your chest or your shoulder.

The muscles, protected by the skin, contain fewer nerve endings, and they are spaced more widely and discontinuously. That is why muscle aches and pains are more diffuse and harder to locate.

The walls of the blood vessels (arteries and veins) are more richly innervated; the free nerve endings that are sensitive to nociceptive stimuli are located in the inner layers of the blood-vessel walls.

In the bones, most of the free nerve endings are located in the marrow and the periosteum, where they form a regular network. Anything that damages the structural integrity of a bone, especially a serious injury such as a fracture, will therefore cause pain.

In the joints, pain receptors are located mainly in the capsule, the synovium, the ligaments, and the tendons. These receptors can be activated either mechanically (tears, strains, etc.) or biochemically (for example, in inflammatory processes such as arthritis.

The internal organs, protected by the skin, muscles, and bones, have even fewer nerve endings than the muscles. The free endings in the internal organs are distributed loosely and very unevenly, which is why pain in these organs is often vague and hard to locate, be it the simple discomfort of indigestion or the violent pain of a kidney stone.

The internal organs most highly innervated with nociceptors are mostly the ones that are hollow (such as the intestines, bladder, and uterus). Because these organs are the internal extension of the outside environment, they are more likely to come into contact with potentially hazardous agents and therefore require proper monitoring. Conversely, solid organs, such as the lungs, liver, and spleen, have fewer free endings and are not highly sensitive to pain. Hence, they can deteriorate without the individual’s becoming very aware of it.


The sense of touch originates in specialized receptors located in the skin. These mechanoreceptors are sensitive both to pressure and to light to moderate stretching. They send messages through the neurons, and the central nervous system interprets these messages as tactile sensations. But when the mechanical pressures on a body tissue become so strong that they threaten its integrity or actually damage it, then the pain receptors, also known as nociceptors, take over.

The nociceptors are free nerve endings: axon tips that have no myelin sheath. They are the highly ramified terminations of A delta fibres and C fibres and are found not only in the skin, but also in muscles, blood vessels, joint, bones, and internal organs (see sidebar)—in short, practically everywhere in the body except the brain itself! Thus, conceptually, a nociceptor refers more to a function (that of feeling pain) than to a specialized kind of receptors (as is the case with mechanoreceptors).

Nociceptors can be activated not only by mechanical stimuli such as pinching, piercing, or biting, but by all kinds of other stimuli that can potentially harm body tissues. Examples include extreme temperatures (see sidebar), electrical shocks, hypoxic conditions (lack of oxygen), or exposure to toxic substances . Some nociceptors are more sensitive to one kind of stimulus rather than to others, but most nociceptors are polymodal, meaning that they can respond to more than one kind of stimulus.

Regardless of the kind of stimulus, it much reach a certain intensity before it can activate the nociceptors (see sidebar), because their activation threshold is higher than that of mechanoreceptors. Hence, by modulating their response according to the intensity of the painful stimulus, nociceptors can encode this intensity. The activation threshold of nociceptors in the skin represent the threshold at which the individual can perceive the sensation of pain.

The structures that let nociceptors sense such a wide range of painful stimuli consist of various types of ion channels located in their cell membranes. Some of these stimuli are direct, such as strong mechanical pressures that deform the membranes and trigger nerve impulses—for example, when you step on the point of a thumbtack, but it does not pierce your skin.

But if you step on a tack and it does pierce the skin, then the damaged cells locally release certain chemicals that indirectly stimulate the nociceptors as well. Some of these “algogenic” (pain-inducing) molecules released by the damaged or inflamed tissue are enzymes such as bradykinin, while others are neurotransmitters such as serotonin, and others are hormones such as prostaglandin. Pain signals can also be generated by an injury to a nerve fibre.

When subjected to strong or repeated pain stimuli, nociceptors undergo sensitization phenomena that lower their response threshold, increasing the number of nerve impulses and the sensation of pain thus produced.


Painful sensations of heat are not produced by excess activity of the same receptors that produce comfortable sensations of heat. Instead, researchers have clearly shown, there are heat nociceptors that are separate and distinct from ordinary heat sensory receptors. When the temperature of a heat stimulus is increased gradually, the activity of the heat sensory receptors increases proportionately up to a temperature of about 45°C, at which point this activity levels off. In contrast, heat nociceptors don’t become active until the temperature reaches 40°, but then their activity increases in proportion to the heat, without reaching a plateau.

And 45°C is just about the temperature at which proteins in the body begin to deteriorate, the body tissues begin to be damaged, and people begin to describe a sensation of heat as painful. But of course, various factors can shift the pain threshold by a few degrees.


Link : Heat Halts Pain Inside The Body



Link : EndorphinLink : Peptides with morphine-like action in the brainLink : Anatomy of a Scientific DiscoveryLink : British Medical Bulletin - Introduction
Link : Biosynthesis of the Enkephalins and Enkephalin-Containing PolypeptidesLink : Characterization of the endorphins, novel hypothalamic and neurohypophysial peptides with opiate-like activity: evidence that they induce profound behavioral changes
Researcher : Hans Walter KosterlitzResearcher : Candace PertResearcher : A Tribute to Dr. Hans Kosterlitz Researcher :  UCSD Guestbook: Solomon Snyder
History : Role of endorphins discoveredHistory : The brain's own opiateHistory : A brief history of opiates, opioid peptides, and opioid receptorsHistory : THE EARLY HISTORY OF THE INRC (1969-1975)
History : histoire des endorphinesHistory : Endorphin and Enkephalin

The terms “opiates” and “opioids” do not mean entirely the same thing.

Medications and other substances are called opiates when they contain opium or any of its derivatives, such as morphine or codeine. Opiate molecules are alkaloids, rather than peptides, and come from a source outside the human body (poppy seeds or synthetic compounds).

The term opioids, on the other hand, refers to a group of peptides that are endogenous to the body and that exert a physiological effect similar to that of morphine. But, in a somewhat circular way, this expression also tends to be used to refer to any substance—natural or synthetic, peptide or not—that acts on what are referred to as the body’s opioid receptors.

Shortly after the discover of natural opioid substances in the brain, people began to associate them with the phenomenon of the “runner’s high”—the intense feeling of well-being that many long-distance runners experience as they cross the finish line. But this same euphoria can also be experienced by anyone who engages in moderately strenuous physical activity for 20 or 30 minutes.

But scientists had remained skeptical about the role of endogenous morphines in producing the runner’s high, among other reasons because in experiments, administering opioid-receptor blockers such as naloxone failed to prevent the subjects from experiencing this sensation.

Some scientists even offered an alternative explanation: that this mood change was actually attributable to another family of molecules, called endocannabinoids, the body’s endogenous cannabis. Like endorphins, endocannabinoids produce their effects by binding to their own specific receptors in the brain—the same ones as THC, the active ingredient in cannabis. Endocannabinoids help to modulate pain. They also induce euphoria, and because their concentration in the body was observed to increase after sustained exercise, researchers hypothesized a connection between these substances and runner’s high.

However, a study published by a group of German researchers in 2008 shifted the focus back to endogenous opioid peptides as the source of runner’s high. First the scientists used a psychological test to assess the mood of 10 human subjects, all of them experienced runners. Then the researchers injected the subjects with a radioactive substance that would reveal the presence of endorphins in their brains in images produced by the brain-scanning method known as positron emission tomography (PET scanning).

Next, the 10 subjects went out running for two hours. When they got back, their mood was assessed once again, and the distribution of radioactivity, and hence of endorphins, in their brains was determined by PET scan. What the researchers found was that the more intense the subjects’ measured feeling of euphoria, the more endorphins were observed in a part of the brain associated with the emotions: the limbic system and the prefrontal cortex.

This study has not identified the precise type of endorphin involved in runner’s high, and further research should be done to make this distinction, because there are so many different types of endorphins, and their effects vary. But an important connection does now seem to have been established: the same substances that have the ability to reduce our perception of intense pain also come into play to offset, and even reverse, the discomfort caused by sustained physical effort.

Link : LA COURSE À PIED DE PLUS DE TRENTE MINUTES LIBÈRE DES ENDORPHINESLink : Yes, Running Can Make You HighLink : L'euphorie du coureurLink : La course à pied est-elle une drogue?
Link : Research Locates Source of Runner's High Experienced by AthletesLink : Endocannabinoids found to spread and prolong painLink : Les receptors aux opiacésLink : Endocannabinoid Mechanisms of Pain Modulation
Tool Module: Brain Imaging

For many centuries, people have been using opium, and various substances derived from it, such as morphine, to relieve pain. The virtues of opium are praised in very early written records, including the cuneiform writing of Sumeria and early Chinese ideograms. But it was not until the 1970s that scientists learned that the human brain also produces its own endogenous morphines. The story of the many discoveries that led to this finding is fascinating in several respects.

First of all, from a scientific standpoint, the researchers made some canny deductions that enabled them to build evidence rapidly. Second, from a technical standpoint, the researchers showed amazing ingenuity and determination, because they had to isolate molecules that occur in very low concentrations in the brain. Lastly, in terms of the sociology of the scientific community, this research effort was remarkable, because it pitted various laboratories in a genuine race against one another while at the same time requiring them to collaborate.

At the start of this effort, scientists knew that opium and its derivatives —substances derived from a plant—had a certain effect on the bodies of animals. In general, for a molecule to affect a cell’s activity, that molecule must bind to receptors, which are usually located in the cell’s membrane. And it is the binding process that, like a key opening a lock, opens the way to a cascade of biochemical phenomena that have a physiological effect—in this case, an analgesic (pain-killing one).

Thus, the first deduction that researchers made, in the early 1970s, was that for these plant-derived opiates to act on animal nerve cells, those cells must have receptors for opiates, just as they had been shown to have for other neurotransmitters. This deduction marked the start of the hunt for opiate receptors, at a time when neurochemistry, the scientific discipline that now deals with such matters, had scarcely begun to emerge.

Convinced that the highly specific effects of morphine (contraction of the pupils, depressed heart rate, reduced perception of pain, and so on) could be produced only if the brain had specific receptors for it, U.S. scientist Solomon Snyder began his research with the most direct approach: he placed radioactive morphine in direct contact with neurons and then attempted to see whether any radioactive molecules had become bound to them. If any had. this was a sign of the presence of receptors on the neurons.

Unfortunately, Snyder found no such molecules bound to the neurons, even when he repeated the experiment with heroin instead of morphine. While the rest of the scientific community was starting to doubt whether opiate receptors even existed, he and his graduate student, Candace Pert, tried their luck one last time, but with a substance called naloxone that was known to block the effects of opiates.

And this time, their luck changed: the radioactive naloxone did remain bound to the neurons! This confirmed the earlier hypothesis that naloxone blocked the effects of morphine by binding to receptors, and most likely to the receptors for morphine itself. With this finding and some further investigation, the researchers realized that in contrast to naloxone molecules, which block receptors by literally becoming trapped in them, morphine and heroin molecules act by binding to receptors for a very short time—too short a time to be detected.

Other researchers, such as Eric Simon and Lars Terenius in 1973, also published similar observations confirming the presence of opiate receptors in the central nervous system. These findings generated a great deal of excitement in the field, because the presence of opiate receptors almost automatically meant that the brain must naturally produce some opiate-like substance to bind to them. In other words, it seemed extremely unlikely that such specific locks would have evolved in the human brain without the keys to open them also being present there (as opposed to keys that had evolved by pure chance in the plant kingdom).

This idea that morphine might simply be mimicking the effects of a substance already present in the body had been in the back of the mind of several scientists who who had worked on isolating the receptor. But it had been especially well defended by the German-born biologist Hans Kosterlitz.

Kosterlitz, working at the University of Aberdeen in Scotland, encouraged the assistant director of his laboratory, John Hughes, to demonstrate the existence of this endogenous morphine. Easy to say, but harder to do, with the tools available at the time. Hughes therefore chose a kind of “morphine detector” that was available to him: the vas deferens of the mouse, because it was already known that the contractions of this tissue were inhibited by morphine binding to specific receptors. The idea was to apply brain extracts to prepared samples of this tissue, and see whether the contractions then ceased.

The problem was that some substances can act at concentrations as low as the equivalent of 1 gram per 10 million litres of water. The chances of success therefore seemed equally infinitesimal, and Hughes had to prowl the slaughterhouses of Aberdeen to collect thousands of pig brains for his laboratory. There he removed certain brain structures, ground them up, concentrated them, and applied them to the mouse vasa deferentia.

In 1973, Hughes found some indications of the presence of an endogenous substance capable of binding to opiate receptors, as did the the laboratory of Lars Terenius in Sweden. These preliminary results were communicated in May 1974. Then, in December 1975, Hughes and Kosterlitz published the structure of two substances that they named enkephalins, from the Greek for “in the head”. Both of these substances were peptides: small proteins formed from just a few amino acids.

Specifically, each of these two enkephalins comprised a sequence of five amino acids, and only the last amino acid in the two sequences was different: methionine in the case of met-enkephalin, and leucine in the case of leu-enkephalin.


In 1976, the teams of Choh Hao Li and Roger Guillemin isolated some longer peptides, endorphins, that also were capable of binding to opiate receptors. Subsequently, many more endogenous opioid peptides, such as the dynorphins, were isolated, so that by 1992, some 20 such substances had been identified.


In 1971, John C. Liebeskind and his colleagues published an article containing some strange observations: stimulating a midbrain region called the periaqueductal grey matter produced pain in laboratory animals, but ceasing the stimulus or reducing its intensity had an analgesic (pain-relieving) effect. This article also suggested that this latter effect was analogous to that of opiate medications. They confirmed their intuition the following year, when they showed that this analgesic effect produced by applying an electrical stimulus, then reducing or removing it, could be prevented by a substance called naloxone that was known to block the effects of opiates.

Liebeskind established many other parallels between the kind of analgesia produced by these stimulations and the effect of opiate medications, thus paving the way to identify descending pain-control mechanisms, opioid receptors, and the first endogenous morphines over the following years.

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