Endorphins: Difference between revisions

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[[File:Met-enkephalin Structure.svg|class=skin-invert-image|thumb|Chemical structure of Met-enkephalin]]
[[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 = 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.&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=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&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>
'''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 ==
== History ==
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== Etymology ==
== 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 (mythology)|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).
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 ==
== Types ==
{{expand section|date=December 2018}}
{{expand section|date=December 2018}}
The class of endorphins consists of three [[Opioid peptide#Endogenous opioids|endogenous opioid]] peptides: [[α-endorphin]], [[β-endorphin]], and [[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.
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" />
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;"
{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
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! Reference
! Reference
|-
|-
| [[α-endorphin]]
| [[α-Endorphin]]
| Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH
| 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" />
| <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]]
| [[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
| 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=http://www.ncbi.nlm.nih.gov/books/NBK470306/ |chapter=Biochemistry, Endorphin  |pmid=29262177 }}</ref><ref name=":1" />
| <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]]
| [[γ-Endorphin]]
| Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH
| Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH
| <ref name=":0"/><ref name="Purves2018" />
| <ref name=":0"/><ref name="Purves2018" />
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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"/>
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==
== 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}}
[[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}}


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== Functions ==
== 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. Biological Sciences | volume = 279 | issue = 1731 | pages = 1161–1167 | date = March 2012 | pmid = 21920973 | pmc = 3267132 | doi = 10.1098/rspb.2011.1373 }}</ref>
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 "[[Neurobiological effects of physical exercise|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, several studies have supported the hypothesis that the runner's high is due to the release of [[endocannabinoids]] rather than that of endorphins.<ref>{{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 }}</ref> Endorphins may contribute to the positive effect of exercise on [[anxiety disorder|anxiety]] and [[major depressive disorder|depression]].<ref>{{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 }}</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>{{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 }}</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==
 
== See also ==
* [[Neurobiological effects of physical exercise]]
* [[Neurobiological effects of physical exercise]]
* [[Enkephalin]]
* [[Enkephalin]]

Latest revision as of 15:44, 1 November 2025

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File:Met-enkephalin Structure.svg
Chemical structure of Met-enkephalin

Endorphins (contracted from endogenous morphine)[1][2][3] 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.[4][5][6][7]

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 Script error: No such module "Lang".) from pig brain, identified as Met-enkephalin and Leu-enkephalin.[8][9][10][11] 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.[11] Research during this time was focused on the search for a painkiller that did not have the addictive character or overdose risk of morphine.[11][12]

Rabi Simantov and Solomon H. Snyder isolated morphine-like peptides from calf brain.[13] Eric J. Simon, who independently discovered opioid receptors, later termed these peptides as endorphins.[14] This term was essentially assigned to any peptide that demonstrated morphine-like activity.[15] 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.[16][17] Li determined that β-endorphin produced strong analgesic effects.[18] 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.[19]

Studies have subsequently distinguished between enkephalins, endorphins, and endogenously produced true morphine,[20][21] 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.[12][22]

Etymology

The word endorphin is derived from Script error: No such module "Lang". / Template:Langx meaning "within" (endogenous, Script error: No such module "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).

Types

Script error: No such module "Unsubst". The class of endorphins consists of three endogenous opioid peptides: α-Endorphin, β-endorphin, and γ-endorphin.[23] 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.[12] 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.[24] 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.[25] 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.[25]

Name Sequence Reference
α-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH [26][12]
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 [27][28]
γ-Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH [26][12]

Synthesis

Endorphin precursors are primarily produced in the pituitary gland.[29][30][31] 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).[32] CPE facilitates POMC transport into immature budding vesicles.[33] In mammals, pro-peptide convertase 1 (PC1) cleaves POMC into adrenocorticotropin (ACTH) and beta-lipotropin (β-LPH).[32] β-LPH, a pituitary hormone with little opiate activity, is then continually fragmented into different peptides, including α-endorphin, β-endorphin, and γ-endorphin.[28][34][35] Peptide convertase 2 (PC2) is responsible for cleaving β-LPH into β-endorphin and γ-lipotropin.[12] Formation of α-endorphin and γ-endorphin results from proteolytic cleavage of β-endorphin.[24]

Regulation

Noradrenaline has been shown to increase endorphins production within inflammatory tissues, resulting in an analgesic effect;[36] the stimulation of sympathetic nerves by electro-acupuncture is believed to be the cause of its analgesic effects.Template:Fact

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.[27][37]

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.[38]Template:Fv Laughter may also stimulate endorphin production and elevate one's pain threshold.[39]

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".[40][41] However, experimental blockade of the mu opioid receptor has shown that endorphins are not strictly necessary for the development of exercise-induced euphoria.[42] It has been suggested that other neurotransmitters, namely endocannabinoids, are more likely contributors.[42][43] Endorphins may partially mediate exercise-induced analgesia.[44]

See also

References

Template:Reflist

External links

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  44. ↑ Script error: No such module "Citation/CS1".
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