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Endorphins are endogenous opioid polypeptide compounds. They are produced by the pituitary gland and the hypothalamus in vertebrates during strenuous exercise, excitement, pain, and orgasm,HYPERLINK \l "cite_noteurlGet_more_than_zeds_in_bed_-_Mind_.26_body_magazine_-_NHS_Direct-2" and they resemble the opiates in their abilities to produce analgesia and a sense of well-being. Endorphins work as "natural fever relievers", whose effects may be enhanced by other medications. The term "endorphin" implies a pharmacological activity (analogous to the activity of the corticosteroid category of biochemicals) as opposed to a specific chemical formulation. It consists of two parts: endo- and -orphin; these are short forms of the words endogenous and morphine, intended to mean "a morphine like substance originating from within the body." The term endorphin rush has been adopted in popular speech to refer to feelings of exhilaration brought on by pain, danger, or other forms of stress, supposedly due to the influence of endorphins. When a nerve impulse reaches the spinal cord, endorphins are released which prevent nerve cells from releasing more pain signals. Endorphins allow someone to immediately after injury feel a sense of power and control over themselves which allows them to persist with activity for an extended time.
Opioid neuropeptides were first discovered in 1975 by two independent groups of investigators. • John Hughes and Hans Kosterlitz of Scotland isolated — from the brain of a pig — what they called enkephalins (from the Greek εγκέφαλος, cerebrum).HYPERLINK \l "cite_note-5" Around the same time in the calf brain, Rabi Simantov and Solomon H. Snyder of the United States found what Eric Simon (who independently discovered opioid receptors in the brain) later termed "endorphin" by an abbreviation of "endogenous morphine", which literally means "morphine produced naturally in the body". Importantly, recent studies have demonstrated that diverse animal and human tissues are in fact capable of producing morphine itself, which is not a peptide.HYPERLINK \l "cite_note-pmid17006413-8"
Mechanism of action
Beta-endorphin is released into the blood (from the pituitary gland) and into the spinal cord and brain from hypothalamic neurons. The beta-endorphin that is released into the blood cannot enter the brain in large quantities because of the blood-brain barrier. The physiological importance of the beta-endorphin that can be measured in the blood is far from clear: beta-endorphin is a cleavage product of pro-opiomelanocortin (POMC) which is also the precursor hormone for adrenocorticotrophic hormone (ACTH). The behavioural effects of beta-endorphin are exerted by its actions in the brain and spinal cord, and probably the hypothalamic neurons are the major source of beta-endorphin at these sites. In situations where the level of ACTH is increased (e.g. Addison disease), the level of endorphins also increases slightly. Beta-endorphin has the highest affinity for the μ1-opioid receptor, slightly lower affinity for the μ2- and δ-opioid receptors and low affinity for the κ1-opioid receptors. μreceptors are the main receptor through which morphine acts. Classically, μ-receptors are presynaptic, and inhibit neurotransmitter release; through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways, causing more dopamine to be released. By hijacking this process, exogenous opioids cause inappropriate dopamine release, and lead to aberrant synaptic plasticity, which causes addiction. Opioid receptors have many other and more important roles in the brain and periphery however, modulating pain, cardiac, gastric and vascular function as well as possibly panic and satiation, and receptors are often found at postsynaptic locations as well as presynaptically.
Scientists debate whether specific activities release measurable levels of endorphins. Much of the current data comes from animal models which may not be relevant to humans. The studies that do involve humans often measure endorphin plasma levels, which do not necessarily correlate with levels in the CNS. Other studies use a blanket opioid antagonist (usually naloxone) to indirectly measure the release of endorphins by observing the changes that occur when any endorphin activity that might be present is blocked. Capsaicin (the active chemical in red chili peppers) also has been shown to stimulate endorphin release. Topical capsaicin has been used as a treatment for certain types of chronic pain.
Another widely publicized effect of endorphin production is the so-called "runner's high", which is said to occur when strenuous exercise takes a person over a threshold that activates endorphin production. Endorphins are released during long, continuous workouts, when the level of intensity is between moderate and high, and breathing is difficult. This also corresponds with the time that muscles use up their stored glycogen. Workouts that are most likely to produce endorphins include, boxing, running, swimming, cross-country skiing, long distance rowing, cycling, hockey, tennis, weight lifting, aerobics, or playing a sport such as soccer, basketball, rugby, lacrosse, Paintball or American football. However, some scientists question the mechanisms at work, their research possibly demonstrating the high comes from completing a challenge rather than as a result of exertion. Studies in the early 1980s cast doubt on the relationship between endorphins and the runner's high for several reasons: • The first was that when an antagonist (pharmacological agent that blocks the action for the substance under study) was infused (e.g. naloxone) or ingested (naltrexone) the same changes in mood state occurred as when the person exercised with no blocker.
A study in 2003 by Georgia Tech found that runner's high might be caused by the release of another naturally produced chemical, Anandamide. Anandamide is similar to the active endocannabinoid anandamide,HYPERLINK \l "cite_note-pmid1462544912" The authors suggest that the body produces this chemical to deal with prolonged stress and pain from strenuous exercise, similar to the original theory involving endorphins. However, the release of anandamide was not reported with the cognitive effects of the runner’s high; this suggests that anandamide release may not be significantly related to runner's high. In 2008, researchers in Germany reported that the myth of the runner's high was not a myth but was in fact true. Using PET scans combined with recently available chemicals that reveal endorphins in the brain, they were able to compare runners’ brains before and after a run. The runners the researchers recruited were told that the opioid receptors in their brains were being studied, and did not realize that their endorphin levels were being studied in regard to the runner's high. The participants were scanned and received psychological tests before and after a twohour run. Data received from the study showed endorphins were produced during the exercise and were attaching themselves to areas of the brain associated with emotions (limbic and prefrontal areas). An investigated possiblity is that a molecule, such as anandamide carries endorphins through the blood-brain barrier, as endorphins are too large to cross the BBB by themselves. If not, endorphins may be produced in the brain itself.
In 1999, clinical researchers reported that inserting acupuncture needles into specific body points triggers the production of endorphins.HYPERLINK \l "cite_notepmid18803495-16" In another study, higher levels of endorphins were found in cerebrospinal fluid after patients underwent acupuncture. In addition, naloxone appeared to block acupuncture’s pain-relieving effects. However, skeptics say that not all studies point to that conclusion, and that in a trial of chronic pain patients, endorphins did not produce long-lasting relief. Endorphins may be released during low levels of pain and physical stimulation when it lasts over 30 minutes. Questions remain as to whether the prolonged low level of pain stimulation as in Capsaicin, acupuncture and running or physical activity alone are the threshold that activates endorphin release.
Definition of Endorphin
Endorphin: One of the body's own painkillers, an opioid (morphine-like) chemical produced by the body that serves to suppress pain. Endorphins are manufactured in the brain, spinal cord, and many other parts of the body. They are released in response to neurotransmitters and bind to certain neuron receptors (the same ones that bind opiate medicines). Endorphins act as analgesics (diminishing the perception of pain) and as sedatives. Chemically, endorphins are peptides (amino acid chains that are shorter than proteins) and they are rapidly inactivated by enzymes called peptidases.
IntroductionPreparations of the opium poppy papaver somniferum have been used for many
hundreds of years to relieve pain. In 1803, Sertürner isolated a crystalline sample of the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the analgesic activity of crude opium. The rigid structural and stereochemical requirements essential for the analgesic actions of morphine and related opioids led to the theory that they produce their effects by interacting with a specific receptor.1 The concept that there is more than one type of opioid receptor arose to explain the dual actions of the synthetic opioid nalorphine, which antagonises the analgesic effect of morphine in man but also acts as an analgesic in its own right. Martin (1967) concluded that the analgesic action of nalorphine is mediated by a receptor, later called the -opioid receptor, that is different from the morphine receptor.2 Evidence for multiple receptors, , and , came from the demonstration of different profiles of pharmacological activity in the chronic spinal dog with the prototype agonists morphine, ketazocine and N-allylnormetazocine (SKF 10047).3 The existence of the -receptor was subsequently proposed to explain the profile of activity in vitro of the enkephalins (the first endogenous opioid peptides), and on the basis of the relative potency of the non-selective opioid antagonist naloxone to reverse endogenous opioid peptide inhibition of the nerve-evoked contractions of the mouse vas deferens.4 Its existence was further confirmed by radioligand binding studies using rat brain homogenates. It is now clear from work carried out in many laboratories over the last 20 years that there are 3 welldefined or "classical" types of opioid receptor µ, and . Genes encoding for these receptors have been cloned.5, 6, 7, 8 More recently, cDNA encoding an "orphan" receptor was identified which has a high degree of homology to the "classical" opioid receptors; on structural grounds this receptor is an opioid receptor and has been named ORL1 (opioid receptor-like).9 As would be predicted from their known abilities to couple through pertussis toxin-sensitive G-proteins, all of the cloned opioid receptors possess the same general structure of an extracellular N-terminal region, seven transmembrane domains and intracellular C-terminal tail structure. There is pharmacological evidence for subtypes of each receptor and other types of novel, less well-characterised opioid receptors, , , , , have also been postulated. The receptor, however, is no longer regarded as an opioid receptor. Receptor Subtypes -Receptor subtypes The MOR-1 gene, encoding for one form of the -receptor, shows approximately 50-70% homology to the genes encoding for the -(DOR-1), -(KOR-1) and orphan (ORL1) receptors. Two splice variants of the MOR-1 gene have been cloned, differing only in the presence or absence of 8 amino acids in the Cterminal tail. The splice variants exhibit differences in their rate of onset and recovery from agonistinduced internalization but their pharmacology does not appear to differ in ligand binding assays.10 Furthermore, in the MOR-1 knockout mouse, morphine does not induce antinociception demonstrating that at least in this species morphine’s analgesia is not mediated through - or -receptors.11 Similarly morphine did not exhibit positive reinforcing properties or an ability to induce physical dependence in the absence of the MOR-1 gene.
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