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Pleasure and pain
Pleasure-Seeking Behaviour
Pleasure and Drugs
Avoiding Pain

HelpLink : Pain And Itch Responses Regulated SeparatelyLink : Factors that Activate NociceptorsLink : Les pains chroniques bientôt soulagées
Link : Sur la piste des pains neuropathiquesLink : Des chercheurs du Douglas identifient une nouvelle protéine reliée à la painLink : Neuronal and Neural-Glial Signaling Mechanisms in Pain NeuroplasticityLink : La pain chronique au tapis
Link : Une protéine associée aux pains chroniquesLink : La douleur chronique démasquéeLink : Social isolation and inflammatory gene expressionLink : Rôle des phénomènes inflammatoires périphériques
Link : Rôle des neurones sensoriels ou nocicepteursLink : Le facteur de croissance des nerfs (NGF) : nouveau rôle d'un médiateur du système nerveux dans le système bronchiqueLink : Role of rat sensory neuron-specific receptor (rSNSR1) in inflammatory pain : Contribution of TRPV1 to SNSR signaling in the pain pathwayLink : Modulation of NMDA receptors by intrathecal administration of the sensory neuron-specific receptor agonist BAM8-22
Link : More advanced pathphysiological processes and nociceptive and nueropathic pain responsesLink : The Central Sensitization Cascade
Researcher : Quirion, RémiResearcher : Activités de recherche de mon laboratoire Dr. Rémi Quirion, Directeur scientifique, INSMTResearcher : Rémi Quirion élargit le champ d'application de la recherche en santé mentaleResearcher : Michael Salter
Original modules
Tool Module : Anaesthesia and AnalgesiaAnaesthesia and Analgesia

Certain nociceptors are described as “silent” because they do not normally respond to any chemical, thermal, or tactile stimulus. But when someone suffers an injury and it becomes inflamed, various molecules associated with the inflammation can lower the activation threshold of these nociceptors, causing them to “wake up” and begin producing action potentials. Many nociceptors in the intestines are silent nociceptors.

Both in central and in peripheral sensitization, there are at least two major mechanisms by which the sensitivity of neurons is increased. The first comes into play within a few minutes of an acute injury, but is only temporary. The second emerges more slowly, over a number of days, but lasts longer. In both cases, the mechanisms are the same as those described in relation to other types of memorization at the cellular level, in particular long-term potentiation.

In the first case, changes occur in proteins that already exist in the cell membrane and that transduce nociceptive stimuli into nerve impulses. For example, these proteins may become phosphorylated, that is, a phosphate group may be added to them by enzymes such as kinases. This phosphorylation changes the form of the proteins, causing them to become, for example, more permeable to certain ions. For instance, the AMPA channel receptor for glutamate is a protein involved in central sensitization. Phosphorylation increases the likelihood that this receptor’s channel will open and the time that it will remain open, thus enabling more sodium ions to enter the neuron and thereby modifying the membrane potential so as to lower the nociceptor’s overall excitability threshold.

If the nociceptive signal persists, then the expression of genes or the speed at which their mRNA is translated into proteins may be increased. If these proteins are new receptors, then they will be taken to the terminal button of the axon, where they too will lower the neuron’s excitability threshold and hence increase its sensitivity.

Many different substances contribute to the sensitization of nociceptors. One of these substances is nerve growth factor (NGF), which is secreted by fibroblasts (support cells in connective tissue) and by cells in the epidermis that have been stimulated by interleukin-1 at the site of an inflammation. The specific receptor for NGF is the TrkA receptor, which occurs on about 50% of all nociceptors. Activation of the TrkA receptor results in phosphorylation of the tyrosine residues in its intracellular portion, as well as phosphorylation of other intracellular molecules such as the TRPV1 receptors (see diagram to right). This phenomenon might explain how NGF increases sensitivity to pain caused by heat.

NGF may also contribute to longer-term sensitization through its ability to modulate the expression of genes such as those for TRPV1 and P2X3. It is known that the complex that NGF forms with its TrkA receptor can be endocytosed by vesicles inside the nerve fibre. Then, by retrograde transport within the axon, the NGF/TrkA complex can ascend all the way back to the nociceptor’s nucleus, where it activates the synthesis of numerous peptides, such as substance P and CGRP. It may then also promote the synthesis of new receptors for the algogenic (pain-producing) peptides secreted at the site of inflammation, such as bradykinin receptors and vanilloid (VR1) receptors.

Link : Immune factors inducing painLink : An NGF-TrkA-Mediated Retrograde Signal to Transcription Factor CREB in Sympathetic NeuronsLink : Les bases neurales de la douleur


Pain is a mechanism that is essential to human survival. Pain normally occurs only in the presence of intense stimuli that are potentially or actually harmful to the body. These stimuli activate high-threshold nerve fibres called nociceptors that relay the pain signals via multiple ascending pathways to the brain.

But unfortunately, when a tissue injury results in inflammation or in damage to the nervous system itself, this acute pain sometimes becomes chronic (in the latter case, it is known as neuropathic pain). Both inflammation and nerve damage can result in pain that arises spontaneously in the absence of any apparent peripheral stimuli, or in hypersensitivity to such stimuli.

The hypersensitivity that occurs after an injury is not bad in itself. It is even adaptive, because it can promote healing by making us avoid letting anything come into contact with the injured tissue. But sometimes this hypersensitivity persists even once the healing is over. In this case, the resulting pain no longer provides any benefits. Instead, it becomes chronic pain, a sign of pathological changes in the nervous system.

Understanding what produces these changes is therefore critically important for treating chronic pain. We do know that two main mechanisms are involved: central sensitization and peripheral sensitization. In both cases, regardless of the underlying mechanisms, the nociceptors become more excitable. In other words, unlike most other human sensory receptors, which react to repeated stimuli by becoming less sensitive, when nociceptors are overstimulated, they become more so.

In the case of central sensitization, this change occurs in the central nervous system, typically at the synapses between the nociceptors affected by a severe, persistent injury and the neurons of the ventral horn of the spinal cord. The injury results in repeated, high-frequency discharges from these nociceptors, which increases the efficiency of their synaptic connections to this part of the central nervous system.

In the injured area, mechanoreceptors that are sensitive to light, tactile stimuli will then start activating neurons in the spinal cord that normally respond to nociceptive stimuli only. The gain in the system is thus increased, so that a piece of clothing simply brushing against the skin can produce a painful sensation. This phenomenon, known as allodynia, is not the only possible consequence of central sensitization. The greater sensitivity that may be felt in intact tissue surrounding the site of an injury is also due to central sensitization and can lead to chronic pain.

This increased system gain is attributable to plasticity phenomena involving NMDA glutamate receptors. Glutamate, an amino acid, is one of the main neurotransmitters released into the synapses by the nociceptors, along with substance P. The binding of large numbers of glutamate molecules to NMDA receptors, modulated by the presence of substance P, induces the biochemical changes that make these central connections more readily excitable.

The resulting pain is known as “wind-up pain”, which may be either temporary or permanent, depending on whether the underlying molecular changes are simple phosphorylations, or more profound changes in the way the genes are expressed (see sidebar). These changes also reduce the effectiveness of the descending control mechanisms that use opioids to alleviate pain.

Such increases in the central nervous system’s nociceptive response to a given stimulus are not the only mechanism that can lead to hypersensitivity. A reduction in the excitation threshold of the nociceptors themselves is another. The term peripheral sensitization is used to describe what happens when these nerve fibres become more sensitive than they were before. One classic example is the change in your skin’s sensitivity that you experience after a sunburn. For example, if you take a shower, a water temperature that would usually feel hot but comfortable may produce pain in the sunburned skin.

Here too, a variety of mechanisms, some faster and others slower (see sidebar), are involved in making the nociceptors’ nerve endings in the affected area more sensitive. When the body suffers an insult sufficient to cause an injury, the damaged cells release their contents into the extracellular space. The resulting “molecular soup” then triggers the secretion of other molecules, in a process known as inflammation. In less than 15 to 30 seconds, dilation of blood vessels causes the area around the injury to redden and become warm to the touch. This inflammatory response, which also causes edema (swelling) and the release of certain chemicals, reaches a peak 5 to 10 minutes later.

The molecules involved in these local biochemical reactions come from various sources, but their first source is the damaged cells themselves. For example, this lysis (cell breakdown) usually releases large numbers of potassium ions, and there is a high correlation between the concentration of potassium and the degree of pain experienced.

The same is true of the extracellular concentration of hydrogen ions, which help to activate ion channels in certain nociceptors directly. This mechanism is responsible, for example, for the muscle pains associated with the production of adenosine triphosphate (ATP) under anaerobic conditions, which generates lactic acid during especially heavy exercise.

Similarly, the ATP from the injured cells contributes to the depolarization of certain nociceptors by directly activating ATP-dependent ion channels.

After a tissue is injured, the surrounding tissue also release substances such as bradykinin (one of the most powerful pain-causing agents known), histamine, and prostaglandins. By binding to their specific receptors on the nociceptors’ cell membranes (see box below), these molecules trigger action potentials in the nociceptive fibres.

Aspirin and other non-steroidal anti-inflammatories are the reference treatment for these hyperalgic phenomena, because they inhibit the enzymes involved in producing prostaglandins.

By a phenomenon known as the axon reflex, the nociceptors also release substance P into their peripheral collaterals, that is, into the areas surrounding the injury. This release of a neurotransmitter in the peripheral nervous system is atypical, because it proceeds in the opposite direction from usual for a sensory neuron (efferent instead of afferent). Its effect is to extend and amplify the pain from the injured area. This release of substance P also causes certain cells, such as mastocytes, to release histamine themselves, thus further activating the nociceptive fibres in this broader area. This is why antihistamine creams that block the histamine receptors can effectively reduce these painful inflammatory reactions.

In addition to releasing substance P peripherally, the nociceptors also release calcitonin gene-related peptides (CGRP). Like substance P, CGRP causes vasodilation both directly, by its effect on smooth muscle tissues, and indirectly, by promoting the release of histamine by the mastocytes. And by causing edema, this local dilation of the capillaries will in turn promote the release of bradykinin.

Many other substances are also involved in peripheral sensitization. One of these is the serotonin released by the blood platelets, which increases the permeability of the capillaries and thus contributes to the inflammatory reaction. Another is nerve growth factor(NGF), which is important for the development and survival of the neurons and also plays a role in inflammatory processes (see sidebar).

Thus we see how complex these biochemical mechanisms are and how they act in two ways simultaneously: not only by activating nociceptors directly, but also by lowering their activation threshold, which is the phenomenon underlying peripheral sensitization.


The nociceptors have numerous transmembrane channels and receptors that are responsible for transducing chemical, mechanical, and thermal stimuli. By modifying the conformation of their target molecules, these stimuli alter the conductance of the cell membrane and hence induce local currents. If the sum of these local currents is high enough, it will then trigger action potentials.

Transient receptor potential (TRP) channels are sensitive to various kinds of nociceptive stimuli. These channels are in a sense “generalists” that play a primary role both in nociception and in other processes of sensory detection. Each TRP is a channel protein composed of six transmembrane sub-units that allow calcium and sodium to enter the nociceptor. For example, sub-type TRPV1 (also known as the vanilloid receptor, VR1) is sensitive not only to capsaicin, but also to the low pH (acidity) created by extracellular protons, as well as to heat. Hence it is truly an integrator of chemical and physical stimuli. Researchers believe that it may also be activated by various kinase proteins, acting through separate biochemical pathways whose details are far from being fully understood.

In contrast, receptors such as acid-sensing ion channels (ASIC) are “specialists” that respond to only one type of stimulus: in this case, extracellular protons, which are either released with the contents of injured cells or produced by anaerobic respiration—for example, in the form of the lactic acid that is generated during heavy exercise and makes muscles painful.

Thus, a single type of stimulus can interact with more than one kind of receptor, as shown by the ability of extracellular protons to activate not only TRPV1 receptors, but ASIC receptors as well.

The process by which stretching and mechanical deformation of tissues is translated into pain signals is still poorly understood. It is thought that proteins in the ENaC/DEG family may act as mechanical transducers not only in the A delta nociceptors, but also in the mechanoreceptors. There are also other candidates among the TRP proteins.

Adapted from Julius and Basbaum, Nature, 2002.

Many other receptors that are modulated by substances given off by inflammatory reactions can contribute to the generation of pain. For example, the extracellular ATP produced by inflammation binds to purinergic receptors, such as P2X3. Activation of the receptors for prostaglandins (PGE2), bradykinin (B1R and B2R), and substance P (NK1) by their respective ligands also contributes to the inflammatory reaction.

This activation often triggers a complex cascade of biochemical reactions. For example, the NK1 receptor is coupled to a G protein and induces the activation of phospholipase C, which cleaves its substrate, phosphatidylinositol biphosphate (PIP2), thus producing inositol triphosphate and diacylglycerol.

An understanding of the operating mechanisms of these various receptors intimately associated with nociception will be essential if researchers are to develop new pain medications. (Existing pain medications, such as opiates and non-steroidal anti-inflammatories , also act on receptors outside the pain pathways, thus producing undesirable side effects.)


Link : L'OxyContin : Parlons franchementLink : L'étude OPICAN, menée dans 7 villes canadiennes, indique que l'abus des opioïdes d'ordonnance est plus répandu que l'usage de l'héroïneLien : Opioid receptorLink : Protéine G
Link : OxycodoneLink : Mood elevating endorphine release greater with social than with solitary exerciseLink : Rowing as a group increases pain thresholdsLink : Endorphins
Lien : Neuroanatomy of PainLink : Peripheral opioid receptors: a new therapeutic concept to target inflammationLink : MedscapeLink : Structure-activity studies on nociceptin/orphanin FQ: from full agonist, to partial agonist, to pure antagonist
Link : Acute pain
Researcher : Jeffrey S. Mogil
Experiment : Induction of Opioid Receptor Function in the Midbrain after Chronic Morphine TreatmentExperiment : Prolonged morphine treatment selectively increases membrane recruitment of ?-opioid receptors in mouse basal ganglia
History : Relief of Pain and Suffering

Chronic use of exogenous opiates reduces the inhibitory effects that endogenous opioid ligands normally have on nociceptive pathways. This reduction is explained in part by a decoupling between the opioid receptors and the G proteins, which short-circuits the cascade of biochemical reactions that normally follow. The opioid receptors themselves are also desensitized, while the synthesis of their natural ligands, such as enkephalins, may be diminished. Lastly, the actual morphology of the neurons is modified by a reduction in the number of neurofilaments and inhibition of axonal transport.

These changes cause profound alterations in the neural activity of the pain circuits. The ultimate outcome is a reduction in the effectiveness of the body’s natural, endorphin-based analgesic system, along with the phenomena of tolerance and dependency.

An agonist is a molecule that acts in the same way as a natural ligand by binding to the same receptor as that ligand. For example, morphine is an agonist of beta-endorphin, because it binds to the same mu receptors and produces similar effects. Methadone, a synthetic compound used to reduce the symptoms of withdrawal from opiates such as heroin and morphine, is also an agonist of the mu receptors.

The antagonist of a molecule is also a molecule that binds to the same receptor as that molecule, but without producing the same effect. Like a key inserted in the wrong lock, an antagonist blocks the receptor by occupying its active site, thereby preventing its natural ligand from binding there. One example of an antagonist that works this way is naloxone, the best known antagonist for opiates.

For example, when someone overdoses on heroin, this molecule binds to their opioid receptors and can thereby reduce their respiration rate to as few as two or three breaths per minute. But if naloxone is administered intravenously, it quickly competes with the heroin in the patient’s blood for the chance to bind to these receptors, and can thereby get the patient’s respiration back up to 15 to 20 breaths per minute in just a few seconds.

More anecdotally, but also revealingly, when people who can eat very strong peppers, such as jalapeños, are injected with opioid antagonists, the enjoyment that these people usually get from these peppers is quickly replaced by terrible pain, because their natural endorphins can no longer do their job.

There are also molecules that are regarded as partial agonists. Partial agonists too occupy the same kind of receptors as a natural ligand and produce the same effect, but with less intensity. Increasing the dose of a partial agonist does increase this effect, but at a certain point, even if the dose continues to be increased, the effect plateaus. At these very high doses, in the presence of the natural ligand, the partial agonist behaves somewhat like an antagonist, gradually displacing the natural ligand from the active sites on the receptors and reducing its effect accordingly.

Buprenorphin is a partial agonist for mu opioid receptors and is used like methadone as a substitution treatment for opiate dependency.

Link : Notion d'agonisteLien : Notion d'antagonisteLink : AgonistLink : Buprénorphine
Link : Methadone

The body’s internal opioid system seems to play a role in psychic dependency on drugs. For example, it has been shown that mice that have no mu opiate receptors will not use a device that lets them self-administer alcohol or cocaine, whereas normal mice will make extensive use of this device to stimulate themselves.

In an other experiment, rats were injected with morphine and then placed in a compartment with walls of one colour. The next day, the rats received a placebo and were placed in another compartment with walls of a different colour. This alternating treatment was repeated several times, and the rats thus learned to associate a particular environment with the pleasurable effects of the morphine.

After this conditioning period, the rats were placed first in one of the two different compartments, and then in the other, without being injected with any drug or placebo. When the rats were placed in the environment associated with the injection of morphine, an increase was observed in the concentration of enkephalins in the synapses of the nucleus accumbens in their brains. But when they were placed in the environment associated with the injection of the placebo, a decrease in this concentration was observed instead.

This production of enkephalins at a key site within the brain’s reward circuit therefore seems to be at least partly involved in the anticipation of a reward. In this connection, it is worth recalling that dopamine, a neurotransmitter closely associated with pleasure, is released under the influence of two types of neuropeptides: on the one hand, cholecystokinins, and on the other, the enkephalins that bind to mu and delta opioid receptors!

Experiment : Endogenous enkephalin modulation of dopamine neurons in ventral tegmental areaExperiment : Mu opioid receptor involvement in enkephalin activation of dopamine neurons in the ventral tegmental areaExperiment : Dopamine Depletion Reorganizes Projections from the Nucleus Accumbens and Ventral Pallidum That Mediate Opioid-Induced Motor Activity

For centuries, opioid substances extracted from plants have been used to ease pain. The discovery of specific membrane receptors for these molecules in the early 1970s and, a few years later, the discovery of endogenous peptides (now known as endorphins) that bind to these same receptors laid the foundations for our understanding of the complex mechanisms of the human endorphin system.

Endorphin receptors are the key elements in the process by which both endorphins and opioid analgesic medications suppress pain (for more details, follow the Anesthesics and Analgesics link to the left). Like most receptors, these endorphin receptors are large proteins embedded in the neuron’s cell membrane.

There are four major families of opioid receptors. All of them consist of proteins that have 7 transmembrane domains. The portion exposed to the extracellular environment has a specific site whose form is complementary to that of the opioid substances that can bind to it. When an opioid binds to such a site, a change occurs in the form of the receptor, which, on the intracellular (cytoplasmic) side, activates a G protein composed of three sub-units (alpha, beta, and gamma).

When the G protein is activated, the guanine diphosphate (GDP) molecule that was bound to its alpha sub-unit is replaced by a molecule of guanine triphosphate (GTP). The GTP in turn causes the alpha-beta-gamma assembly to break down into an alpha sub-unit and a beta-gamma sub-unit.

Adapted from Molecular Pharmacology Laboratory
web site, Monash University, Australia

Each of these two entities then contributes to the transduction of the signal. In other words, each of them triggers a cascade of biochemical reactions inside the cell following a triggering event outside the cell (the molecules involved in this cascade are often referred to as “second messengers”). When the event outside the cell is the binding of an endogenous opioid peptide or an opiate of external origin to an opioid receptor, the effects of this cascade on the activity of the nerve cell are generally inhibitory.

Adapted from Molecular Pharmacology Laboratory
web site, Monash University, Australia

Among the inhibitory mechanisms involved, the ones about which the most is known involve adenylate cyclase, an enzyme that converts ATP into cyclic AMP. Cyclic AMP is an important second messenger that interacts with several other proteins, and the reduction of ATP into cyclic AMP is the origin, for example, of the hyperpolarization observed in neurons when mu or delta agonists bind to their opioid receptors. In this case, the cyclic AMP affects potassium channels to produce the decline in neuronal excitability known as hyperpolarization.

Another effect of the cascade of second messengers that the G protein initiates inside the neuron is to reduce the calcium permeability of the voltage-sensitive calcium channels in the axon’s terminal button (near the synapse). As a result, in the case of afferent nociceptive C fibre axons, the amount of neurotransmitters (particularly substance P and glutamate) released into the synapse is reduced.

The resulting weakened transmission of the nerve impulse by the presynaptic neuron has the same effect as the raising of the threshold for triggering action potentials (hyperpolarization) in the post-synaptic neuron: reduced overall activity in the ascending pain pathways (see sidebar) and hence reduced perception of pain.

Each of the major families of opioid receptors also comprises various sub-types that may be selectively activated by certain ligands. The effects of these ligands will differ not only according to the particular nature of the receptor sub-type to which they bind, but also according to the type of neuron on which these receptors are located.

At least four major families of opioid receptors are known to exist. They are designated by the Greek letters mu, delta, and kappa and by the abbreviation ORL1 (where ORL stands for “opioid-receptor-like”).

Delta opioid receptors were the first type to be described, in the mid-1970s. Enkephalins are the type of endorphins that have the greatest affinity for delta receptors and are therefore considered their natural ligands. (Enkephalins can also bind to mu and kappa receptors, but have less of an affinity for them.)
Link : Récepteurs opioïdesLink : Delta Opioid receptorLink : The delta receptorResearcher : Louis Gendron, Ph.D.

Researchers initially had difficulty in characterizing delta receptors, because natural enkephalins have such a short lifespan. But a bit more has been learned about delta receptors since researchers succeeded in synthesizing the peptides that are specific to them. For example, we now know that activation of the delta receptors produces analgesia, though to a lesser extent than activation of the mu receptors. On the other hand, this analgesia resulting from activation of the delta receptors also seems to produce fewer undesirable side effects, and in particular less depressed breathing, constipation, and tolerance. Researchers are therefore investigating the treatment of chronic pain with agonists (see definition in sidebar) that are selective for delta receptors.

Another interesting characteristic of delta receptors is their effect in regulating mood. Studies have shown that mutant mice that did not have the gene for the delta receptor displayed higher levels of anxiety and depressive behaviour. Here again, agonists specific to delta receptors may prove invaluable in the treatment of mood disorders.

Delta receptors are blocked by naloxone, but this opioid receptor antagonist (see definition in sidebar) has less of an affinity to bind with delta receptors than with mu receptors.

Adapted from “Mu-opioid receptor model (inactive state) with antagonist”, Mosberg Lab, University of Michigan

Link : How Does The Opioid System Control Pain, Reward And Addictive Behavior?Link : mu Opioid receptorLink : Mu Opioid Receptor Regulation And Opiate Responsiveness

For mu opioid receptors , the natural ligand is beta-endorphin, which was the second opioid peptide to be identified after the enkephalins. Enkephalins too bind with a high affinity to mu receptors, but dynorphins do not: their affinity for mu receptors is low.

Mu receptors are also the preferential binding sites for morphine and the other exogenous opioid derivatives. However, these morphine-based analgesics produce undesirable side effects, such as depressed breathing, constipation, and tolerance, mainly by way of the mu receptor.

Modern methods of molecular biology have enabled researchers to identify multiple variants of the gene for the mu receptor. One subtype, mu1, is more associated with the analgesic effect, and the other, mu2, with the effects on breathing and intestinal motility.

It has also been proposed that mu receptors may play a role in bonding between mothers and children, as well as in the reward circuit. This latter role might be the source of the dependency behaviours induced by substances such as ethyl alcohol, nicotine, heroin, and morphine. One piece of evidence for this hypothesis is that mice in which the mu receptors have been deactivated do not develop such dependencies.

The distribution of mu receptors in the nervous system corresponds to their effects. For example, these receptors are present in large numbers in the brainstem centres that control breathing, as well as presynaptically in the periaqueductal grey matter and the dorsal horn of the spinal cord, where they contribute to the descending inhibition of pain.

This descending control, which is also involved in the placebo effect, is blocked by naloxone, a powerful antagonist for mu receptors.

Kappa opioid receptors have the greatest affinity for dynorphin, an opioid peptide discovered in the late 1970s. But these receptors too have various subtypes, and they differ in their affinity for dynorphin. Like the other opioid receptors, kappa receptors induce analgesia but also cause nausea, as well as dysphoria and other undesirable psychological effects, which adds to the difficulties of developing synthetic agonists for this kind of receptor.
Link : kappa Opioid receptorLink : Opposing actions of the ?-opioid receptorExperiment : The Effect of κ-Opioid Receptor Agonists on Tetrodotoxin-Resistant Sodium Channels in Primary Sensory NeuronsExperiment : The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System

Researchers have also found numerous connections between chronic stress, its harmful effects on health, and dynorphins. The body’s dynorphin system, and hence ultimately the kappa receptors that are part of it, are believed to control certain neural circuits associated with the state of permanent tension known as stress, thus producing the dysphoric effects associated with it.

More generally, there is a growing body of data showing that activation of the kappa receptors produces effects that oppose those arising from the activation of the mu receptors, such as analgesia, tolerance, reward, and memory. These opposing effects would also imply that these two types of receptors are located on different categories of neurons in the circuits where opioid peptides are used.

Link : kappa Opioid receptorLink : Opposing actions of the ?-opioid receptor
The most recently discovered type of opioid receptor is the nociceptin receptor, also known as ORL1 (where ORL stands for “opioid-receptor-like”). This receptor has a high affinity for nociceptin (also known as orphanin), but a very low affinity for the three other major families of endorphins. And conversely, opioid peptides other than nociceptin scarcely bind at all to ORL1 receptors.

This is a fairly singular finding, given that the structure of the ORL1 receptor is so similar to that of the three other classes of opioid receptors. The singularity continues in terms of the functioning of the ORL1 receptor: depending on the amount of nociceptin and the site, this receptor may sometimes act as an antagonist to the effects of opiates, and sometimes as an analgesic itself. The activation of the ORL1 receptor is also believed to affect levels of dopamine either directly or indirectly (through the neurotransmitter GABA). Thus, according to the data currently available, the pharmacology of the ORL1 receptor appears to be highly complex.


Endorphins and their receptors are very widely distributed throughout the supraspinal, spinal, and peripheral parts of the nervous system and are especially numerous in the areas involved in the descending control of pain.

Supraspinally, the presence of opioid receptors in the periaqueductal grey matter is very well documented and has been shown in autoradiographic studies. Microinjections of morphine into this structure have been shown to have a highly analgesic effect, as has electrical stimulation. This effect could be blocked by naloxone, an opioid-receptor antagonist (see the second sidebar in this section), etc.

The release of endorphin into the periaqueductal grey matter can normally be triggered by nociceptive stimuli from the spinal cord as well as by the connections from many other structures in the brainstem and higher centres.

Other likely supraspinal sites for the release of endorphins include the reticular formation, the substantia nigra, the raphe nuclei, the hypothalamus, the hippocampus, the caudate nucleus, the amygdala, and the ventral prefrontal cortex.

Spinally, opioid receptors are located in the axon terminals of C fibres and in the cell bodies of nociceptive neurons in the surface layers of the dorsal horn of the spinal cord.

Many interneurons located near the axon terminals of the C and A delta fibres in these surface layers of the spinal cord release enkephalins as neurotransmitters. These enkephalins can be released by the activation of the serotonergic fibres from the reticular formation. The entryway for the nociceptive signal can thus be blocked either by a reduction in the substance P or glutamate secreted by the C or A delta fibres, or by a reduction in the excitability of the nociceptive neurons of the spinal cord. But both are the result of the binding of enkephalins to their specific receptors.

Peripherally, opioid receptors have been identified in the terminations of many sensory fibres, in particular nociceptive C fibres. The three main types of opioid receptors are produced in the cell bodies of these neurons (located in the spinal ganglia) and carried by the axons to the peripheral terminations.

The analgesic effect mediated by these peripheral opioid receptors would appear to be especially strong in nociceptive fibres that have already been sensitized by inflammation. Tissue injuries also stimulate the expression of opioid receptors.

When an opioid medication is administered either orally or intravenously, it will thus exert its analgesic effects at several levels. The fact that some immune cells also express opioid receptors indicates that these effects might be broader still.


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