endorphin

n.
Any of a group of peptide hormones that bind to opiate receptors and are found mainly in the brain. Endorphins reduce the sensation of pain and affect emotions.

[ENDO(GENOUS) + (MO)RPHIN(E).]

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A family of endogenous morphinelike peptides present within the central nervous system. The term endorphin is generic, referring to all the opioid peptides, while specific peptides are given individual names, such as the enkephalins and β-endorphin. Their discovery has greatly enhanced the understanding of the mechanism of action of opiate drugs and how the perception of pain is modulated within the central nervous system. See also Opiates; Pain.

Morphine, codeine, and their many synthetic and semisynthetic analogs are effective pain killers that act through specific recognition sites, or receptors, localized on the surface of neurons within selected brain regions. These receptors have been extensively characterized, and a number of different subtypes have been identified which vary in their specificity for various opiates and opioid peptides and in the actions they mediate. The existence of these highly specific receptors implied that morphine was mimicking endogenous compounds within the brain with morphinelike actions, which have since been termed endorphins.

The first endorphins to be isolated were the enkephalins, two pentapeptides differing only in their fifth amino acid, which is either methionine or leucine. Since the initial description of the enkephalins, a number of opioid peptides have been reported that all share either the structure of methionine (Met) enkephalin or leucine (Leu) enkephalin as their first five amino acids. The major genes for these peptides have been identified. β-Endorphin is perhaps the most interesting peptide; it is cogenerated with important, nonopioid hormones.

The enkephalins are distributed unevenly throughout the brain, with very high levels in the basal ganglia, the thalamus, and the periaqueductal gray. In addition, there are high concentrations of enkephalins in the adrenal medulla, where they are co-released with norepinephrine in response to stress, among other stimuli. The dynorphins and α-endorphin are located within the central nervous system with a distribution similar to that of the enkephalins. See also Stress (psychology).

β-Endorphin has been identified in only a single group of cells within the hypothalamus. Its highest levels are in the pituitary gland. Within the pituitary, both ACTH and β-endorphin are derived from the same precursor protein and are located within the same cells. Stimuli that release ACTH, a stress hormone which in turn induces the adrenal gland to release steroids, also co-release β-endorphin at the same time. Thus, stressful stimuli that release ACTH and norepinephrine also release both β-endorphin from the pituitary and enkephalins from the adrenal into the blood. This is particularly intriguing in view of the decreased perception of pain reported under periods of stress, such as combat. See also Endocrine system (vertebrate).

All the endorphins can modulate the intensity of pain despite the fact that they act through different classes of opiate receptors. However, the presence of high concentrations of endorphins in brain regions unrelated to pain perception clearly demonstrates that the full range of actions of these compounds within the brain is not yet fully understood. Furthermore, their systemic hormonal role remains uncertain. See also Nervous system (vertebrate).

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During the 1960s and early 1970s, it became apparent that opioid drugs such as morphine and heroin produced their profound actions in the body by interacting with specific receptors on the outer membrane of nerve cells. This raised the intriguing question of why the body goes to the trouble of synthesizing such receptor proteins. Surely it was not just on the off chance that a drug such as morphine might be administered. In 1975 the group in Aberdeen, Scotland led by Hans Kosterlitz and John Hughes, isolated from the pig brain two related molecules, the enkephalins, which bind to and activate opioid receptors. These enkephalins are short peptides, each comprising five amino acids. Although at first glance the enkephalins did not look similar in chemical composition to morphine, they proved to have a crucial component in common. We now know that the brain contains as many as thirteen such endogenous (internally generated) opioid peptides, which have come to be referred to collectively as ‘endorphins’.

There are three classically defined opioid receptor types, named the m, d, and k receptors, and each of the endorphins shows a different spectrum of activation (agonist action) at these different receptors. The endorphins function as inhibitory neurotransmitters and neurohormones: they are released from nerve cells to act on other cells that bear opioid receptors and thus dampen the activity of those cells.

To probe the physiological functions of the endogenous opioid systems, either antagonist drugs can be administered or transgenic mice lacking one or more of the receptors can be developed. From such studies it is evident that the endorphins play little part in our normal routine daily functions. If, in ordinary circumstances, one were to be given an opioid antagonist such as naloxone, little change would be observed. It is when the body is stressed that the endorphins are important. Then they are released to activate their receptors and help to protect the body. Thus endorphins interacting with the m and d receptors have been implicated in the inability of some accident victims to sense the severe pain that their injuries should be causing and also in the ‘high’ that is experienced following exercise. Endogenous opioids may also be responsible for part of the analgesia experienced during acupuncture therapy.

Recently a new, endogenous neuropeptide system, very closely associated with the endogenous opioid system, has been discovered. Unfortunately, at present the terminology used to label the receptor and its endogenous peptide agonist is still quite clumsy. The receptor is referred to as the ORL1 receptor, and the endogenous peptide that is an agonist at the receptor is called either nociceptin or orphanin FQ. The term ‘nociceptin’ derives from the initial belief that this peptide acts in the opposite direction to the endorphins in that, rather than being pain relieving, it actually enhances pain (cf. noxious, from the Latin noceo, to injure). It is becoming apparent that this is an oversimplification and that this peptide in some circumstances inhibits the action of morphine and the endorphins but in other circumstances can also itself suppress pain.

What is very exciting is that this new system appears to be involved in other important brain functions apart from the sensation of pain. The discovery that it may be involved in memory, anxiety, and appetite control make it an exciting new area for drug development. Several major pharmaceutical companies are currently developing non-peptide molecules (more stable and brain-penetrating than the peptides) that will act as agonists and antagonists at the ORL1 receptor, to advance our knowledge of the physiological and pathophysiological functions of this receptor. Hopefully this will result in the discovery of novel therapeutic agents.

— G. Henderson

See also analgesia; opiates and opioid drugs; membrane receptors; peptides.

A group of painkilling chemicals secreted by the brain. Endorphins, like encephalins, are produced naturally and have effects similar to those of artificial narcotics such as morphine and heroin. The release of endorphins is believed to increase during prolonged exercise. This may explain the development of conditions such as runner's high in which exercisers experience a sense of elation during prolonged, vigorous activity. There is also a theory that the pain relief induced by acupuncture and transcutaneous nerve stimulation is due to the release of endorphins.

(en′dorfins)
n.pl

Substances produced in the brain and pituitary gland that reduce pain sensations by binding to receptors in the nervous system. The three endorphins, called alpha-, beta-, and gamma-endorphin, are subsequences of the 91-amino-acid peptide hormone, beta-lipotropin.

A peptide found in the gut, brain, and pituitary gland, which acts as neurotransmitter. Endorphins, like enkephalins, are endogenous opiates. They can bind onto opiate receptors in the brain and mimic the analgesic effect of morphine. The release of endorphins is believed to increase when an athlete gets his or her second wind. Endorphins may be responsible for some of the pleasant feelings associated with exercise, such as runner's high.

Endorphins and closely related chemicals called enkephalins are part of a larger group called opiods, which have properties very much like drugs such as heroin or morphine. They can act not only as pain killers but also can induce a sense of well-being or euphoria. Clinical applications of endorphin research include possible treatments for some forms of mental illness; treatment or control of pain for chronic pain sufferers; development of new anesthetics; and the development of non-addictive, safe, and effective pain relievers.

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(en-dawr-finz)

Substances produced by the brain that have painkilling and tranquillizing effects on the body. Endorphins are thought to be similar to morphine and are usually released by the brain during times of extreme body stress. The release of endorphins may explain why trauma victims sometimes cannot feel the pain associated with their injuries.

One of the major classes of peptides that occur in the brain. They appear to take part in the transmission of chemical messages between nerve cells by acting on receptors which have the characteristic property of binding opiate compounds such as morphine.

It has been known for a very long time that certain plant extracts contain opiates and that these compounds have powerful effects on behaviour, mood, and pain (see opium). Only recently, however, was the question asked whether the presence of opiate receptor sites indicated the existence of naturally occurring opiate-like compounds in the nervous system itself. In 1975 the first successful extraction of such endogenous compounds was achieved. They were called encephalins (literally: in the brain). Originally two distinct forms were found. Both were peptides with five amino acid constituents in the sequence, differing from each other only at one site and named methionine–encephalin and leucine–encephalin.

Following this breakthrough, many more active endogenous compounds were found. They all contain the same opioid core of five amino acids found in encephalin. It is now clear that they can be grouped into three genetically different peptide families with different distributions in the nervous system. The situation appears to be similar to that found for another family of neurotransmitter substances — the monoamines, where modification in the basic chemical structure is associated with their distribution in several anatomically distinct groups of neurons.

1. Three opioid peptide families
2. Functions

1. Three opioid peptide families

It has been known for some time that hormones secreted into the gut are synthesized initially as high-molecular-weight precursors, and that the active hormones are produced by cleavage of a fragment or several fragments from the precursor before they act at receptor sites. This same principle appears to hold true for hormones secreted from the pituitary gland and for the opioids in the brain and pituitary. The three precursors for the opioids are called pro-opiomelanocortin (POMC), proencephalin, and prodynorphin. The POMC molecule, in addition to containing the encephalin sequence, contains another opioid peptide of very high potency, and two other hormone sequences, one for adrenocorticotrophic hormone (which stimulates the adrenal cortex) and one for melanocyte-stimulating hormone (which regulates skin pigmentation). Proencephalin contains several peptides all of which have opioid activity, while prodynorphin is a simpler precursor than the other two and produces three main opioids.

As is the case for many other neurotransmitters, there appear to be several types of receptor for the opioids. This may reflect differing mechanisms for translating opioid effects into different responses or the presence of several types of opioid compound within a given synaptic terminal, or the different anatomical distribution of the three main opioid families (see below), or all these possibilities together. For example, slight variations in the structure of the peptide sequence may result in subtly differing effects at the opiate receptor, particularly when these variations occur in the amino acids adjacent to the central encephalin sequence. It is possible to imagine a wide range of activity at receptors resulting from such modifications, which, when they act at different receptor subtypes, confer an enormous dynamic range of responsiveness. In addition, receptor super- or subsensitivity resulting from long-term functional adaptation may add further to the complexity of effects. The picture becomes even more complicated by the discovery that transmitters may coexist in the same synaptic terminal. It was thought that neurons used only one transmitter to exert their effects at chemical synapses, but this assumption collapsed. Many examples are now described where a low-molecular-weight transmitter such as acetylcholine or noradrenaline (norepinephrine) coexists with a peptide. One example is the co-presence of encephalin and noradrenaline in the adrenal medulla, an endocrine gland. The significance of the phenomenon of coexistence is unknown, but it may be related to the slow time course of action of many neuropeptides. Thus the peptide may modulate the responsiveness of a neuron to its partner transmitter in some way, perhaps to sharpen or broaden the time resolution of the synaptic message. These properties may confer further subtlety on neuronal events, which may allow us to transcend the simple idea that excitation or inhibition in a neural network is the only information subject to coding, translation, and transformation.Anatomy of the opioid systems. In the brain the main POMC cell group lies in the arcuate nucleus of the hypothalamus and it sends axons to innervate many limbic and brain-stem regions. Another small group of neurons lies in the brain-stem centres that regulate autonomic functions (such as cardiovascular control). In the pituitary gland POMC is synthesized mainly in the intermediate lobe and in a few anterior lobe cells.

The most abundant type are neurons which synthesize proencephalin. They are distributed widely in the brain from the highest cortical to the lowest spinal levels, as both long axon and short axon pathways. In the peripheral neuroendocrine system, proencephalin-derived peptides are also found in the adrenal medulla, the gut, and many other structures.

Prodynorphin is found in the gut, posterior pituitary, and brain, where it is located chiefly in the hypothalamus, basal ganglia, and brain stem.

2. Functions

The distribution of opioids indicates that they participate in many different brain functions and (in a broad sense) probably in every brain function. For technical reasons, however, some areas have received more attention than others. These are mechanisms of pain sensation, cardiovascular regulation, hypotensive shock, and endocrine activity. More complex systems controlling feeding, drinking, movement, motivation, reinforcement, memory, mood, and affect are also influenced by opioids but little is known of their effects in these difficult areas.Pain and stress. The experimental finding that brain stimulation of specific sites produces a reduction in pain responses, which can be reversed by the specific opiate antagonist naloxone, suggests that endogenous opiates are involved in analgesic mechanisms (see anaesthesia). Furthermore, pain relief is accompanied by increased opioid levels in the cerebrospinal fluid which circulates around the brain.

Analgesia may also be produced by repeated stressful stimuli. This is accompanied by a reduction in hypothalamic opioids, perhaps because the material is released by the stimulus. Stress-induced analgesia may also be counteracted by opiate receptor-blocking drugs. The sites of action and neural circuits involved are far from clear, however, and they must involve non-opiate as well as opiate pathways. In addition, stress-induced analgesia may depend partly on opioids released from the pituitary gland or peripheral organs such as the adrenal glands. Thus the adrenal medulla stores and releases both the catecholamines and encephalin together in responses to stress.

An interesting finding has been obtained in relation to the phenomenon of placebo analgesia. Here subjects may report relief of pain even when given a dummy tablet. Those reporting analgesia following an inactive placebo show raised opioid concentrations in the circulation. No matter where the opioid is generated, the result suggests that physiological processes may be influenced by the belief of the subject that an analgesic substance has been given. The implications of this finding would appear to be quite far reaching.Circulation and endocrine control. The anatomical distribution of the three opioid families suggests that they all play a role in the central regulation of cardiovascular functions. Thus, all three are present in neurons of the brain-stem cardiovascular regulatory centres. The POMC family is present in the anterior pituitary which influences the adrenal cortex and hence blood pressure, and the prodynorphin group acts on posterior pituitary hormones to control blood volume. Furthermore, the encephalins of the sympathetic nervous system, via their control of the vascular bed, are well placed to regulate regional blood flow and hence blood pressure.

These fundamental discoveries feed through to applications of importance to medical treatment. For example, the state of shock resulting from loss of blood is a dangerous condition which is difficult to treat. Since naloxone, by blocking opiate receptors probably located in the brain, can reverse shock-induced reduction in blood volume, it is possible that more effective management of this condition will soon be available.

See also brain function and awareness; neuronal connectivity and brain function; psychopharmacology.

— O. T. Phillipson

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One of a group of opiate-like peptides produced naturally by the body at neural synapses at various points in the central nervous system pathways where they modulate the transmission of pain perceptions. The term endorphin was coined by combining the words endogenous and morphine. Like morphine, endorphins raise the pain threshold and produce sedation and euphoria; the effects are blocked by naloxone, a narcotic antagonist.

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Endorphin