View source for Endorphins

{{Short description|Hormones and neuropeptides}}
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{{Other uses}}
{{Use dmy dates|date=February 2015}}
[[File:Met-enkephalin Structure.svg|class=skin-invert-image|thumb|Chemical structure of Met-enkephalin]]

'''Endorphins''' (contracted from '''endogenous morphine''')<ref name="Endogenous steroids in humans">{{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 = https://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.&nbsp;... 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).&nbsp;... Human white blood cells have the ability to make and release morphine }}</ref><ref name="IUPHAR">{{cite web|date=15 March 2017|title=μ receptor|url=https://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&nbsp;... Morphine occurs endogenously.}}</ref><ref name="Chotima2004">{{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 }}</ref> are [[peptide]]s 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]] [[painkiller]]s often produced in the brain and [[adrenal medulla]] during [[physical exercise]] or [[orgasm]] and inhibit pain, [[muscle cramps]], and relieve stress.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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}}</ref>

== History ==
[[Opioid peptide]]s in the brain were first discovered in 1973 by investigators at the University of Aberdeen, [[John Hughes (neuroscientist)|John Hughes]] and [[Hans Kosterlitz]]. They isolated "[[enkephalin]]s" (from the [[Greek language|Greek]] {{lang|el|εγκέφαλος}}) from [[pig]] [[brain]], identified as Met-enkephalin and Leu-enkephalin.<ref name="pbs.org">{{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}}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref name="Corbett2006">{{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 }}</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">{{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 }}</ref>

Rabi Simantov and [[Solomon H. Snyder]] isolated morphine-like peptides from [[calf (animal)|calf]] brain.<ref>{{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 }}</ref> [[Eric J. Simon]], who independently discovered opioid receptors, later termed these peptides as endorphins.<ref name="pmid1195988">{{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 }}</ref> This term was essentially assigned to any peptide that demonstrated morphine-like activity.<ref name="McLaughlin2020">{{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 }}</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>{{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 }}</ref><ref name=":6">{{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 }}</ref> Li determined that β-endorphin produced strong analgesic effects.<ref>{{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 }}</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>{{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 }}</ref>

Studies have subsequently distinguished between enkephalins, endorphins, and endogenously produced true [[morphine]],<ref name="pmid15383669">{{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 }}</ref><ref name="pmid17006413">{{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 }}</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>{{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 }}</ref>

== 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 ==
{{expand section|date=December 2018}}
The class of endorphins consists of three [[Opioid peptide#Endogenous opioids|endogenous opioid]] peptides: [[α-Endorphin]], [[β-Endorphin|β-endorphin]], and [[γ-Endorphin|γ-endorphin]].<ref name="Endogenous opioid families - 2012 review">{{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 }}</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">{{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 }}</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">{{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 }}</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" />

{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
|-
! 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">{{cite journal | vauthors = Ling N, Burgus R, Guillemin R | title = Isolation, primary structure, and synthesis of alpha-endorphin and gamma-endorphin, two peptides of hypothalamic-hypophysial origin with morphinomimetic activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 11 | pages = 3942–3946 | date = November 1976 | pmid = 1069261 | pmc = 431275 | doi = 10.1073/pnas.73.11.3942 | doi-access = free | bibcode = 1976PNAS...73.3942L }}</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">{{cite book |last1=Chaudhry |first1=Shazia R. |last2=Gossman |first2=William |title=StatPearls |date=2024 |publisher=StatPearls Publishing |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK470306/ |chapter=Biochemistry, Endorphin  |pmid=29262177 }}</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" />
|}

== Synthesis ==
Endorphin precursors are primarily produced in the [[pituitary gland]].<ref>{{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 }}</ref><ref name=":42">{{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 }}</ref><ref>{{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 }}</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">{{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 }}</ref> CPE facilitates POMC transport into immature budding vesicles.<ref>{{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 }}</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">{{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 }}</ref><ref name=":2">{{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 }}</ref><ref name=":3">{{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 }}</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"/>

== Regulation ==
[[Norepinephrine|Noradrenaline]] has been shown to increase endorphins production within inflammatory tissues, resulting in an [[Analgesic|analgesic effect]];<ref>{{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 }}</ref> the stimulation of [[Sympathetic nervous system|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.<ref name=":4" /><ref>{{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 }}</ref>

== 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.<ref name=":5">{{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 }}</ref>{{fv|date=December 2023}} [[Laughter]] may also stimulate endorphin production and elevate one's [[Threshold of pain|pain threshold]].<ref>{{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 of the Royal Society B: Biological Sciences| volume = 279 | issue = 1731 | pages = 1161–1167 | date = March 2012 | pmid = 21920973 | pmc = 3267132 | doi = 10.1098/rspb.2011.1373 }}</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>{{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 }}</ref><ref>{{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}}</ref> However, experimental blockade of the mu opioid receptor has shown that endorphins are not strictly necessary for the development of exercise-induced euphoria.<ref name=":7">{{Cite web |title=News: Getting to the Bottom of the Runner's... (The New York Times) - Behind the headlines - NLM |url=https://www.ncbi.nlm.nih.gov/search/research-news/12949 |access-date=2025-07-04 |website=NCBI |language=en}}</ref> It has been suggested that other neurotransmitters, namely [[endocannabinoids]], are more likely contributors.<ref name=":7" /><ref>{{Cite journal |last1=Siebers |first1=Michael |last2=Biedermann |first2=Sarah V. |last3=Fuss |first3=Johannes |date=June 2023 |title=Do Endocannabinoids Cause the Runner's High? Evidence and Open Questions |journal=The Neuroscientist |volume=29 |issue=3 |pages=352–369 |doi=10.1177/10738584211069981 |issn=1089-4098 |pmc=10159215 |pmid=35081831}}</ref> Endorphins may partially mediate exercise-induced analgesia.<ref>{{Cite journal |last1=Anderson |first1=Elizabeth |last2=Shivakumar |first2=Geetha |date=2013 |title=Effects of exercise and physical activity on anxiety |journal=Frontiers in Psychiatry |volume=4 |pages=27 |doi=10.3389/fpsyt.2013.00027 |doi-access=free |issn=1664-0640 |pmc=3632802 |pmid=23630504}}</ref>

== See also ==
* [[Neurobiological effects of physical exercise]]
* [[Enkephalin]]

== References ==
{{reflist|30em}}

== External links ==
* {{MeshName|Endorphins}}
{{Hormones}}
{{Opioid peptides}}
{{Chocolate}}

{{Authority control}}
[[Category:Opioid peptides]]
[[Category:Analgesics]]
[[Category:Neuropeptides]]
[[Category:Stress (biological and psychological)]]
[[Category:Stress (biology)]]
[[Category:Psychological stress]]
[[Category:Motivation]]
[[Category:Pain]]
[[Category:Grief]]
[[Category:Anxiety]]
[[Category:Happy hormones]]