Endorphins

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Chemical structure of Met-enkephalin

Endorphins (contracted from endogenous morphine)<ref name="Endogenous steroids in humans">Template:Cite journal</ref><ref name="IUPHAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name"Chotima2004">Template:Cite journal</ref> are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

HistoryEdit

Opioid peptides in the brain were first discovered in 1973 by investigators at the University of Aberdeen, John Hughes and Hans Kosterlitz. They isolated "enkephalins" (from the Greek {{#invoke:Lang|lang}}) from pig brain, identified as Met-enkephalin and Leu-enkephalin.<ref name="pbs.org">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref name="Corbett2006">Template:Cite journal</ref> This came after the discovery of a receptor that was proposed to produce the pain-relieving analgesic effects of morphine and other opioids, which led Kosterlitz and Hughes to their discovery of the endogenous opioid ligands.<ref name="Corbett2006" /> Research during this time was focused on the search for a painkiller that did not have the addictive character or overdose risk of morphine.<ref name="Corbett2006" /><ref name="Purves2018">Template:Cite book</ref>

Rabi Simantov and Solomon H. Snyder isolated morphine-like peptides from calf brain.<ref>Template:Cite journal</ref> Eric J. Simon, who independently discovered opioid receptors, later termed these peptides as endorphins.<ref name="pmid1195988">Template:Cite journal</ref> This term was essentially assigned to any peptide that demonstrated morphine-like activity.<ref name="McLaughlin2020">Template:Cite book</ref> In 1976, Choh Hao Li and David Chung recorded the sequences of α-, β-, and γ-endorphin isolated from camel pituitary glands for their opioid activity.<ref>Template:Cite journal</ref><ref name=":6">Template:Cite journal</ref> Li determined that β-endorphin produced strong analgesic effects.<ref>Template:Cite journal</ref> Wilhelm Feldberg and Derek George Smyth in 1977 confirmed this, finding β-endorphin to be more potent than morphine. They also confirmed that its effects were reversed by naloxone, an opioid antagonist.<ref>Template:Cite journal</ref>

Studies have subsequently distinguished between enkephalins, endorphins, and endogenously produced true morphine,<ref name="pmid15383669">Template:Cite journal</ref><ref name="pmid17006413">Template:Cite journal</ref> which is not a peptide. Opioid peptides are classified based on their precursor propeptide: all endorphins are synthesized from the precursor proopiomelanocortin (POMC), encoded by proenkephalin A, and dynorphins encoded by pre-dynorphin.<ref name="Purves2018" /><ref>Template:Cite journal</ref>

EtymologyEdit

The word endorphin is derived from {{#invoke:Lang|lang}} / Template:Langx meaning "within" (endogenous, {{#invoke:Lang|lang}} / Template:Langx, "proceeding from within"), and morphine, from Morpheus (Template:Langx), the god of dreams in the Greek mythology. Thus, endorphin is a contraction of 'endo(genous) (mo)rphin' (morphin being the old spelling of morphine).

TypesEdit

Template:Expand section The class of endorphins consists of three endogenous opioid peptides: α-endorphin, β-endorphin, and γ-endorphin.<ref name="Endogenous opioid families - 2012 review">Template:Cite journal</ref> The endorphins are all synthesized from the precursor protein, proopiomelanocortin, and all contain a Met-enkephalin motif at their N-terminus: Tyr-Gly-Gly-Phe-Met.<ref name="Purves2018" /> α-endorphin and γ-endorphin result from proteolytic cleavage of β-endorphin between the Thr(16)-Leu(17) residues and Leu(17)-Phe(18) respectively.<ref name=":562">Template:Cite journal</ref> α-endorphin has the shortest sequence, and β-endorphin has the longest sequence.

α-endorphin and γ-endorphin are primarily found in the anterior and intermediate pituitary.<ref name=":8">Template:Cite book</ref> While β-endorphin is studied for its opioid activity, α-endorphin and γ-endorphin both lack affinity for opiate receptors and thus do not affect the body in the same way that β-endorphin does. Some studies have characterized α-endorphin activity as similar to that of psychostimulants and γ-endorphin activity to that of neuroleptics separately.<ref name=":8" />

Name	Sequence	Reference
α-endorphin	Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH	<ref name=":0">Template:Cite journal</ref><ref name="Purves2018" />
β-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	<ref name=":4">Template:Cite book</ref><ref name=":1" />
γ-endorphin	Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH	<ref name=":0"/><ref name="Purves2018" />

SynthesisEdit

Endorphin precursors are primarily produced in the pituitary gland.<ref>Template:Cite journal</ref><ref name=":42">Template:Cite journal</ref><ref>Template:Cite journal</ref> All three types of endorphins are fragments of the precursor protein proopiomelanocortin (POMC). At the trans-Golgi network, POMC binds to a membrane-bound protein, carboxypeptidase E (CPE).<ref name=":432">Template:Cite journal</ref> CPE facilitates POMC transport into immature budding vesicles.<ref>Template:Cite journal</ref> In mammals, pro-peptide convertase 1 (PC1) cleaves POMC into adrenocorticotropin (ACTH) and beta-lipotropin (β-LPH).<ref name=":432" /> β-LPH, a pituitary hormone with little opiate activity, is then continually fragmented into different peptides, including α-endorphin, β-endorphin, and γ-endorphin.<ref name=":1">Template:Cite journal</ref><ref name=":2">Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> Peptide convertase 2 (PC2) is responsible for cleaving β-LPH into β-endorphin and γ-lipotropin.<ref name="Purves2018" /> Formation of α-endorphin and γ-endorphin results from proteolytic cleavage of β-endorphin.<ref name=":562"/>

RegulationEdit

Noradrenaline has been shown to increase endorphins production within inflammatory tissues, resulting in an analgesic effect;<ref>Template:Cite journal</ref> the stimulation of sympathetic nerves by electro-acupuncture is believed to be the cause of its analgesic effects.Template:Fact

Mechanism of actionEdit

Endorphins are released from the pituitary gland, typically in response to pain, and can act in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the PNS, β-endorphin is the primary endorphin released from the pituitary gland. Endorphins inhibit transmission of pain signals by binding μ-receptors of peripheral nerves, which block their release of neurotransmitter substance P. The mechanism in the CNS is similar but works by blocking a different neurotransmitter: gamma-aminobutyric acid (GABA). In turn, inhibition of GABA increases the production and release of dopamine, a neurotransmitter associated with reward learning.<ref name=":4" /><ref>Template:Cite journal</ref>

FunctionsEdit

Endorphins play a major role in the body's inhibitory response to pain. Research has demonstrated that meditation by trained individuals can be used to trigger endorphin release.<ref name=":5">Template:Cite journal</ref>Template:Fv Laughter may also stimulate endorphin production and elevate one's pain threshold.<ref>Template:Cite journal</ref>

Endorphin production can be triggered by vigorous aerobic exercise. The release of β-endorphin has been postulated to contribute to the phenomenon known as "runner's high".<ref>Template:Cite journal</ref><ref>Template:Cite news</ref> However, several studies have supported the hypothesis that the runner's high is due to the release of endocannabinoids rather than that of endorphins.<ref>Template:Cite news</ref> Endorphins may contribute to the positive effect of exercise on anxiety and depression.<ref>Template:Cite journal</ref> The same phenomenon may also play a role in exercise addiction. Regular intense exercise may cause the brain to downregulate the production of endorphins in periods of rest to maintain homeostasis, causing a person to exercise more intensely in order to receive the same feeling.<ref>Template:Cite journal</ref>