Endorphins
{{Short description|Hormones and neuropeptides}}
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File:Met-enkephalin Structure.svg
Endorphins (contracted from endogenous morphine){{cite journal | vauthors = Stefano GB, Ptáček R, Kuželová H, Kream RM | title = Endogenous morphine: up-to-date review 2011 | journal = Folia Biologica | volume = 58 | issue = 2 | pages = 49–56 | date = 1515 | doi = 10.14712/fb2012058020049 | pmid = 22578954 | url = http://fb.cuni.cz/file/5635/FB2012A0008.pdf | quote = Positive evolutionary pressure has apparently preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla. ... The apparently serendipitous finding of an opiate alkaloid-sensitive, opioid peptide-insensitive, µ3 opiate receptor subtype expressed by invertebrate immunocytes, human blood monocytes, macrophage cell lines, and human blood granulocytes provided compelling validating evidence for an autonomous role of endogenous morphine as a biologically important cellular signalling molecule (Stefano et al., 1993; Cruciani et al., 1994; Stefano and Scharrer, 1994; Makman et al., 1995). ... Human white blood cells have the ability to make and release morphine }}{{cite web|date=15 March 2017|title=μ receptor|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=319|access-date=28 December 2017|work=IUPHAR/BPS Guide to PHARMACOLOGY|publisher=International Union of Basic and Clinical Pharmacology|quote=Comments: β-Endorphin is the highest potency endogenous ligand ... Morphine occurs endogenously.}}{{cite journal | vauthors = Poeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH | title = Endogenous formation of morphine in human cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 39 | pages = 14091–14096 | date = September 2004 | pmid = 15383669 | pmc = 521124 | doi = 10.1073/pnas.0405430101 | doi-access = free | bibcode = 2004PNAS..10114091P }} 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.{{cite journal | vauthors = Pilozzi A, Carro C, Huang X | title = Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism | journal = International Journal of Molecular Sciences | volume = 22 | issue = 1 | pages = 338 | date = December 2020 | pmid = 33396962 | pmc = 7796446 | doi = 10.3390/ijms22010338 | doi-access = free }}{{cite journal | vauthors = Howlett TA, Tomlin S, Ngahfoong L, Rees LH, Bullen BA, Skrinar GS, McArthur JW | title = Release of beta endorphin and met-enkephalin during exercise in normal women: response to training | journal = British Medical Journal | volume = 288 | issue = 6435 | pages = 1950–1952 | date = June 1984 | pmid = 6329401 | pmc = 1442192 | doi = 10.1136/bmj.288.6435.1950 }}{{cite journal | vauthors = Goldfarb AH, Jamurtas AZ | title = Beta-endorphin response to exercise. An update | journal = Sports Medicine | volume = 24 | issue = 1 | pages = 8–16 | date = July 1997 | pmid = 9257407 | doi = 10.2165/00007256-199724010-00002 }}{{Cite web |title=Endorphins: What They Are and How to Boost Them |url=https://my.clevelandclinic.org/health/body/23040-endorphins |access-date=2023-03-25 |website=Cleveland Clinic |language=en}}
History
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 {{lang|el|εγκέφαλος}}) from pig brain, identified as Met-enkephalin and Leu-enkephalin.{{cite web|date=1 January 1998|title=Role of endorphins discovered|url=https://www.pbs.org/wgbh/aso/databank/entries/dh75en.html|access-date=15 October 2008|work=PBS Online: A Science Odyssey: People and Discoveries|publisher=Public Broadcasting System}}{{cite journal | vauthors = Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR | title = Identification of two related pentapeptides from the brain with potent opiate agonist activity | journal = Nature | volume = 258 | issue = 5536 | pages = 577–580 | date = December 1975 | pmid = 1207728 | doi = 10.1038/258577a0 | bibcode = 1975Natur.258..577H }}{{cite book | vauthors = Berezniuk I, Fricker LD | chapter = Endogenous Opioids|date=2011 | title = The Opiate Receptors|pages=93–120 | veditors = Pasternak GW|series=The Receptors|place=Totowa, NJ | publisher=Humana Press|language=en |doi=10.1007/978-1-60761-993-2_5 |isbn=978-1-60761-993-2 }}{{cite journal | vauthors = Corbett AD, Henderson G, McKnight AT, Paterson SJ | title = 75 years of opioid research: the exciting but vain quest for the Holy Grail | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S153–S162 | date = January 2006 | pmid = 16402099 | pmc = 1760732 | doi = 10.1038/sj.bjp.0706435 }} 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. Research during this time was focused on the search for a painkiller that did not have the addictive character or overdose risk of morphine.{{Cite book |url=https://books.google.com/books?id=4xoGDQEACAAJ |title=Neuroscience|date=2018 | vauthors = Purves D, Fitzpatrick D, Augustine GJ |isbn=9781605353807 |location=New York | publisher = Sunderland |oclc=990257568|edition=6th }}
Rabi Simantov and Solomon H. Snyder isolated morphine-like peptides from calf brain.{{cite journal | vauthors = Simantov R, Snyder SH | title = Morphine-like peptides in mammalian brain: isolation, structure elucidation, and interactions with the opiate receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 7 | pages = 2515–2519 | date = July 1976 | pmid = 1065904 | pmc = 430630 | doi = 10.1073/pnas.73.7.2515 | doi-access = free | bibcode = 1976PNAS...73.2515S }} Eric J. Simon, who independently discovered opioid receptors, later termed these peptides as endorphins.{{cite journal | vauthors = Goldstein A, Lowery PJ | title = Effect of the opiate antagonist naloxone on body temperature in rats | journal = Life Sciences | volume = 17 | issue = 6 | pages = 927–931 | date = September 1975 | pmid = 1195988 | doi = 10.1016/0024-3205(75)90445-2 }} This term was essentially assigned to any peptide that demonstrated morphine-like activity.{{cite book | vauthors = McLaughlin PJ, Zagon IS | chapter = POMC-Derived Opioid Peptides|date=2013 | title = Handbook of Biologically Active Peptides|pages=1592–1595|publisher=Elsevier |language=en|doi=10.1016/b978-0-12-385095-9.00217-7|isbn=978-0-12-385095-9 }} 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.{{cite journal | vauthors = Li CH, Chung D | title = Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 4 | pages = 1145–1148 | date = April 1976 | pmid = 1063395 | pmc = 430217 | doi = 10.1073/pnas.73.4.1145 | doi-access = free | bibcode = 1976PNAS...73.1145L }}{{cite journal | vauthors = Smyth DG | title = 60 YEARS OF POMC: Lipotropin and beta-endorphin: a perspective | journal = Journal of Molecular Endocrinology | volume = 56 | issue = 4 | pages = T13–T25 | date = May 2016 | pmid = 26903509 | doi = 10.1530/JME-16-0033 | doi-access = free }} Li determined that β-endorphin produced strong analgesic effects.{{cite journal | vauthors = Loh HH, Tseng LF, Wei E, Li CH | title = beta-endorphin is a potent analgesic agent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 8 | pages = 2895–2898 | date = August 1976 | pmid = 8780 | pmc = 430793 | doi = 10.1073/pnas.73.8.2895 | doi-access = free | bibcode = 1976PNAS...73.2895L }} 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.{{cite journal | vauthors = Feldberg W, Smyth DG | title = C-fragment of lipotropin--an endogenous potent analgesic peptide | journal = British Journal of Pharmacology | volume = 60 | issue = 3 | pages = 445–453 | date = July 1977 | pmid = 560894 | pmc = 1667279 | doi = 10.1111/j.1476-5381.1977.tb07521.x }}
Studies have subsequently distinguished between enkephalins, endorphins, and endogenously produced true morphine,{{cite journal | vauthors = Poeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH | title = Endogenous formation of morphine in human cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 39 | pages = 14091–14096 | date = September 2004 | pmid = 15383669 | pmc = 521124 | doi = 10.1073/pnas.0405430101 | doi-access = free | bibcode = 2004PNAS..10114091P }}{{cite journal | vauthors = Kream RM, Stefano GB | title = De novo biosynthesis of morphine in animal cells: an evidence-based model | journal = Medical Science Monitor | volume = 12 | issue = 10 | pages = RA207–RA219 | date = October 2006 | pmid = 17006413 | url = https://medscimonit.com/abstract/index/idArt/459203 }} 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.{{cite journal | vauthors = Stein C | title = Opioid Receptors | journal = Annual Review of Medicine | volume = 67 | issue = 1 | pages = 433–451 | date = 2016-01-14 | pmid = 26332001 | doi = 10.1146/annurev-med-062613-093100 | doi-access = free }}
Etymology
The word endorphin is derived from {{lang|grc|ἔνδον}} / {{langx|el|éndon}} meaning "within" (endogenous, {{lang|grc|ἐνδογενής}} / {{langx|el|endogenes}}, "proceeding from within"), and morphine, from Morpheus ({{langx|grc|Μορφεύς|translit=Morpheús}}), 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).
Types
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The class of endorphins consists of three endogenous opioid peptides: α-endorphin, β-endorphin, and γ-endorphin.{{cite journal | vauthors = Li Y, Lefever MR, Muthu D, Bidlack JM, Bilsky EJ, Polt R | title = Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins | journal = Future Medicinal Chemistry | volume = 4 | issue = 2 | pages = 205–226 | date = February 2012 | pmid = 22300099 | pmc = 3306179 | doi = 10.4155/fmc.11.195 }} 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. 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.{{cite journal | vauthors = Burbach JP | title = Action of proteolytic enzymes on lipotropins and endorphins: biosynthesis, biotransformation and fate | journal = Pharmacology & Therapeutics | volume = 24 | issue = 3 | pages = 321–354 | date = January 1984 | pmid = 6087385 | doi = 10.1016/0163-7258(84)90008-1 | hdl-access = free | hdl = 1874/25178 }} 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.{{cite book |doi=10.1016/S0079-6123(08)64588-4 |chapter=Chapter 29 Endorphins and schizophrenia |title=The Human Hypothalamus in Health and Disease, Proceedings of the 17th International Summer School of Brain Research, held at the Auditorium of the University of Amsterdam |series=Progress in Brain Research |date=1992 |volume=93 |pages=433–453 |isbn=978-0-444-89538-7 | vauthors = Wiegant VM, Ronken E, Kovács G, De Wied D }} 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.
Synthesis
Endorphin precursors are primarily produced in the pituitary gland.{{cite journal | vauthors = Burbach JP | title = Action of proteolytic enzymes on lipotropins and endorphins: biosynthesis, biotransformation and fate | journal = Pharmacology & Therapeutics | volume = 24 | issue = 3 | pages = 321–354 | date = January 1984 | pmid = 6087385 | doi = 10.1016/0163-7258(84)90008-1 | hdl-access = free | hdl = 1874/25178 }}{{cite journal | vauthors = Mousa SA, Shakibaei M, Sitte N, Schäfer M, Stein C | title = Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain | journal = Endocrinology | volume = 145 | issue = 3 | pages = 1331–1341 | date = March 2004 | pmid = 14630714 | doi = 10.1210/en.2003-1287 | doi-access = free }}{{cite journal | vauthors = Takahashi A, Mizusawa K | title = Posttranslational modifications of proopiomelanocortin in vertebrates and their biological significance | journal = Frontiers in Endocrinology | volume = 4 | pages = 143 | date = October 2013 | pmid = 24146662 | pmc = 3797980 | doi = 10.3389/fendo.2013.00143 | doi-access = free }} 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).{{cite journal | vauthors = Mousa SA, Shakibaei M, Sitte N, Schäfer M, Stein C | title = Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain | journal = Endocrinology | volume = 145 | issue = 3 | pages = 1331–1341 | date = March 2004 | pmid = 14630714 | doi = 10.1210/en.2003-1287 | doi-access = free }} CPE facilitates POMC transport into immature budding vesicles.{{cite journal | vauthors = Loh YP, Kim T, Rodriguez YM, Cawley NX | title = Secretory granule biogenesis and neuropeptide sorting to the regulated secretory pathway in neuroendocrine cells | journal = Journal of Molecular Neuroscience | volume = 22 | issue = 1–2 | pages = 63–71 | date = 2004 | pmid = 14742911 | doi = 10.1385/jmn:22:1-2:63 }} In mammals, pro-peptide convertase 1 (PC1) cleaves POMC into adrenocorticotropin (ACTH) and beta-lipotropin (β-LPH). β-LPH, a pituitary hormone with little opiate activity, is then continually fragmented into different peptides, including α-endorphin, β-endorphin, and γ-endorphin.{{cite journal | vauthors = Ambinder RF, Schuster MM | title = Endorphins: new gut peptides with a familiar face | journal = Gastroenterology | volume = 77 | issue = 5 | pages = 1132–1140 | date = November 1979 | pmid = 226450 | doi = 10.1016/S0016-5085(79)80089-X | doi-access = free }}{{cite journal | vauthors = Crine P, Gianoulakis C, Seidah NG, Gossard F, Pezalla PD, Lis M, Chrétien M | title = Biosynthesis of beta-endorphin from beta-lipotropin and a larger molecular weight precursor in rat pars intermedia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 75 | issue = 10 | pages = 4719–4723 | date = October 1978 | pmid = 216997 | pmc = 336191 | doi = 10.1073/pnas.75.10.4719 | doi-access = free | bibcode = 1978PNAS...75.4719C }}{{cite journal | vauthors = Goldstein A | title = Opioid peptides endorphins in pituitary and brain | journal = Science | volume = 193 | issue = 4258 | pages = 1081–1086 | date = September 1976 | pmid = 959823 | doi = 10.1126/science.959823 | bibcode = 1976Sci...193.1081G }} Peptide convertase 2 (PC2) is responsible for cleaving β-LPH into β-endorphin and γ-lipotropin. Formation of α-endorphin and γ-endorphin results from proteolytic cleavage of β-endorphin.
Regulation
Noradrenaline has been shown to increase endorphins production within inflammatory tissues, resulting in an analgesic effect;{{cite journal | vauthors = Binder W, Mousa SA, Sitte N, Kaiser M, Stein C, Schäfer M | title = Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue | journal = The European Journal of Neuroscience | volume = 20 | issue = 1 | pages = 92–100 | date = July 2004 | pmid = 15245482 | doi = 10.1111/j.1460-9568.2004.03459.x }} the stimulation of sympathetic nerves by electro-acupuncture is believed to be the cause of its analgesic effects.{{fact|date=December 2024}}
Mechanism of action
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.{{cite journal | vauthors = Sprouse-Blum AS, Smith G, Sugai D, Parsa FD | title = Understanding endorphins and their importance in pain management | journal = Hawaii Medical Journal | volume = 69 | issue = 3 | pages = 70–71 | date = March 2010 | pmid = 20397507 | pmc = 3104618 }}
Functions
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.{{cite journal | vauthors = Dfarhud D, Malmir M, Khanahmadi M | title = Happiness & Health: The Biological Factors- Systematic Review Article | journal = Iranian Journal of Public Health | volume = 43 | issue = 11 | pages = 1468–1477 | date = November 2014 | pmid = 26060713 | pmc = 4449495 }}{{fv|date=December 2023}} Laughter may also stimulate endorphin production and elevate one's pain threshold.{{cite journal | vauthors = Dunbar RI, Baron R, Frangou A, Pearce E, van Leeuwen EJ, Stow J, Partridge G, MacDonald I, Barra V, van Vugt M | display-authors = 6 | title = Social laughter is correlated with an elevated pain threshold | journal = Proceedings. Biological Sciences | volume = 279 | issue = 1731 | pages = 1161–1167 | date = March 2012 | pmid = 21920973 | pmc = 3267132 | doi = 10.1098/rspb.2011.1373 }}
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".{{cite journal | vauthors = Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR | display-authors = 6 | title = The runner's high: opioidergic mechanisms in the human brain | journal = Cerebral Cortex | volume = 18 | issue = 11 | pages = 2523–2531 | date = November 2008 | pmid = 18296435 | doi = 10.1093/cercor/bhn013 | doi-access = free }}{{Cite news|url=https://www.nytimes.com/2008/03/27/health/nutrition/27best.html|title=Yes, Running Can Make You High| vauthors = Kolata G |date=2008-03-27|newspaper=The New York Times |access-date=2016-05-26}} However, several studies have supported the hypothesis that the runner's high is due to the release of endocannabinoids rather than that of endorphins.{{Cite news| vauthors = Reynolds G |date=2021-03-10|title=Getting to the Bottom of the Runner's High|language=en-US|work=The New York Times|url=https://www.nytimes.com/2021/03/10/well/move/running-exercise-mental-effects.html|access-date=2021-03-16 }} Endorphins may contribute to the positive effect of exercise on anxiety and depression.{{cite journal | vauthors = Anderson E, Shivakumar G | title = Effects of exercise and physical activity on anxiety | journal = Frontiers in Psychiatry | volume = 4 | pages = 27 | date = 2013-04-23 | pmid = 23630504 | pmc = 3632802 | doi = 10.3389/fpsyt.2013.00027 | doi-access = free }} 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.{{cite journal | vauthors = Freimuth M, Moniz S, Kim SR | title = Clarifying exercise addiction: differential diagnosis, co-occurring disorders, and phases of addiction | journal = International Journal of Environmental Research and Public Health | volume = 8 | issue = 10 | pages = 4069–4081 | date = October 2011 | pmid = 22073029 | pmc = 3210598 | doi = 10.3390/ijerph8104069 | doi-access = free }}
See also
References
{{reflist|30em}}
External links
- {{MeshName|Endorphins}}
{{Hormones}}
{{Opioid peptides}}
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