Biology:Endorphins

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Short description: Hormones and neuropeptides


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 εγκέφαλος, cerebrum) 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 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 ἔνδον / Greek: éndon meaning "within" (endogenous, ἐνδογενής / Greek: endogenes, "proceeding from within"), and morphine, from Morpheus (Ancient Greek:), 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

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.[37]

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][38]

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.[39][failed verification] Laughter may also stimulate endorphin production and elevate one's pain threshold.[40]

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".[41][42] However, several studies have supported the hypothesis that the runner's high is due to the release of endocannabinoids rather than that of endorphins.[43] Endorphins may contribute to the positive effect of exercise on anxiety and depression.[44] 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.[45]

References

  1. ↑ "Endogenous morphine: up-to-date review 2011". Folia Biologica 58 (2): 49–56. 1515. PMID 22578954. http://fb.cuni.cz/file/5635/FB2012A0008.pdf. "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". 
  2. ↑ "μ receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. 15 March 2017. http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=319. "Comments: β-Endorphin is the highest potency endogenous ligand ... Morphine occurs endogenously." 
  3. ↑ "Endogenous formation of morphine in human cells". Proceedings of the National Academy of Sciences of the United States of America 101 (39): 14091–14096. September 2004. doi:10.1073/pnas.0405430101. PMID 15383669. Bibcode: 2004PNAS..10114091P. 
  4. ↑ "Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism". International Journal of Molecular Sciences 22 (1): 338. December 2020. doi:10.3390/ijms22010338. PMID 33396962. 
  5. ↑ "Release of beta endorphin and met-enkephalin during exercise in normal women: response to training". British Medical Journal 288 (6435): 1950–1952. June 1984. doi:10.1136/bmj.288.6435.1950. PMID 6329401. 
  6. ↑ "Beta-endorphin response to exercise. An update". Sports Medicine 24 (1): 8–16. July 1997. doi:10.2165/00007256-199724010-00002. PMID 9257407. 
  7. ↑ "Endorphins: What They Are and How to Boost Them" (in en). https://my.clevelandclinic.org/health/body/23040-endorphins. 
  8. ↑ "Role of endorphins discovered". PBS Online: A Science Odyssey: People and Discoveries. Public Broadcasting System. 1 January 1998. https://www.pbs.org/wgbh/aso/databank/entries/dh75en.html. 
  9. ↑ "Identification of two related pentapeptides from the brain with potent opiate agonist activity". Nature 258 (5536): 577–580. December 1975. doi:10.1038/258577a0. PMID 1207728. Bibcode: 1975Natur.258..577H. 
  10. ↑ "Endogenous Opioids" (in en). The Opiate Receptors. The Receptors. Totowa, NJ: Humana Press. 2011. pp. 93–120. doi:10.1007/978-1-60761-993-2_5. ISBN 978-1-60761-993-2. 
  11. ↑ 11.0 11.1 11.2 "75 years of opioid research: the exciting but vain quest for the Holy Grail". British Journal of Pharmacology 147 (Suppl 1): S153–S162. January 2006. doi:10.1038/sj.bjp.0706435. PMID 16402099. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Neuroscience (6th ed.). New York: Sunderland. 2018. ISBN 9781605353807. OCLC 990257568. https://books.google.com/books?id=4xoGDQEACAAJ. 
  13. ↑ "Morphine-like peptides in mammalian brain: isolation, structure elucidation, and interactions with the opiate receptor". Proceedings of the National Academy of Sciences of the United States of America 73 (7): 2515–2519. July 1976. doi:10.1073/pnas.73.7.2515. PMID 1065904. Bibcode: 1976PNAS...73.2515S. 
  14. ↑ "Effect of the opiate antagonist naloxone on body temperature in rats". Life Sciences 17 (6): 927–931. September 1975. doi:10.1016/0024-3205(75)90445-2. PMID 1195988. 
  15. ↑ "POMC-Derived Opioid Peptides" (in en). Handbook of Biologically Active Peptides. Elsevier. 2013. pp. 1592–1595. doi:10.1016/b978-0-12-385095-9.00217-7. ISBN 978-0-12-385095-9. 
  16. ↑ "Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands". Proceedings of the National Academy of Sciences of the United States of America 73 (4): 1145–1148. April 1976. doi:10.1073/pnas.73.4.1145. PMID 1063395. Bibcode: 1976PNAS...73.1145L. 
  17. ↑ "60 YEARS OF POMC: Lipotropin and beta-endorphin: a perspective". Journal of Molecular Endocrinology 56 (4): T13–T25. May 2016. doi:10.1530/JME-16-0033. PMID 26903509. 
  18. ↑ "beta-endorphin is a potent analgesic agent". Proceedings of the National Academy of Sciences of the United States of America 73 (8): 2895–2898. August 1976. doi:10.1073/pnas.73.8.2895. PMID 8780. Bibcode: 1976PNAS...73.2895L. 
  19. ↑ "C-fragment of lipotropin--an endogenous potent analgesic peptide". British Journal of Pharmacology 60 (3): 445–453. July 1977. doi:10.1111/j.1476-5381.1977.tb07521.x. PMID 560894. 
  20. ↑ "Endogenous formation of morphine in human cells". Proceedings of the National Academy of Sciences of the United States of America 101 (39): 14091–14096. September 2004. doi:10.1073/pnas.0405430101. PMID 15383669. Bibcode: 2004PNAS..10114091P. 
  21. ↑ "De novo biosynthesis of morphine in animal cells: an evidence-based model". Medical Science Monitor 12 (10): RA207–RA219. October 2006. PMID 17006413. 
  22. ↑ "Opioid Receptors". Annual Review of Medicine 67 (1): 433–451. 2016-01-14. doi:10.1146/annurev-med-062613-093100. PMID 26332001. 
  23. ↑ "Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins". Future Medicinal Chemistry 4 (2): 205–226. February 2012. doi:10.4155/fmc.11.195. PMID 22300099. 
  24. ↑ 24.0 24.1 "Action of proteolytic enzymes on lipotropins and endorphins: biosynthesis, biotransformation and fate". Pharmacology & Therapeutics 24 (3): 321–354. January 1984. doi:10.1016/0163-7258(84)90008-1. PMID 6087385. 
  25. ↑ 25.0 25.1 Endorphins and schizophrenia. Progress in Brain Research. 93. 1992. pp. 433–53. 
  26. ↑ 26.0 26.1 "Isolation, primary structure, and synthesis of alpha-endorphin and gamma-endorphin, two peptides of hypothalamic-hypophysial origin with morphinomimetic activity". Proceedings of the National Academy of Sciences of the United States of America 73 (11): 3942–3946. November 1976. doi:10.1073/pnas.73.11.3942. PMID 1069261. Bibcode: 1976PNAS...73.3942L. 
  27. ↑ 27.0 27.1 "Biochemistry, Endorphin". StatPearls. StatPearls Publishing. 2018. http://www.ncbi.nlm.nih.gov/books/NBK470306/. Retrieved 2019-02-20. 
  28. ↑ 28.0 28.1 "Endorphins: new gut peptides with a familiar face". Gastroenterology 77 (5): 1132–1140. November 1979. doi:10.1016/S0016-5085(79)80089-X. PMID 226450. 
  29. ↑ "Action of proteolytic enzymes on lipotropins and endorphins: biosynthesis, biotransformation and fate". Pharmacology & Therapeutics 24 (3): 321–354. January 1984. doi:10.1016/0163-7258(84)90008-1. PMID 6087385. 
  30. ↑ "Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain". Endocrinology 145 (3): 1331–1341. March 2004. doi:10.1210/en.2003-1287. PMID 14630714. 
  31. ↑ "Posttranslational modifications of proopiomelanocortin in vertebrates and their biological significance". Frontiers in Endocrinology 4: 143. October 2013. doi:10.3389/fendo.2013.00143. PMID 24146662. 
  32. ↑ 32.0 32.1 "Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain". Endocrinology 145 (3): 1331–1341. March 2004. doi:10.1210/en.2003-1287. PMID 14630714. 
  33. ↑ "Secretory granule biogenesis and neuropeptide sorting to the regulated secretory pathway in neuroendocrine cells". Journal of Molecular Neuroscience 22 (1–2): 63–71. 2004. doi:10.1385/jmn:22:1-2:63. PMID 14742911. 
  34. ↑ "Biosynthesis of beta-endorphin from beta-lipotropin and a larger molecular weight precursor in rat pars intermedia". Proceedings of the National Academy of Sciences of the United States of America 75 (10): 4719–4723. October 1978. doi:10.1073/pnas.75.10.4719. PMID 216997. Bibcode: 1978PNAS...75.4719C. 
  35. ↑ "Opioid peptides endorphins in pituitary and brain". Science 193 (4258): 1081–1086. September 1976. doi:10.1126/science.959823. PMID 959823. Bibcode: 1976Sci...193.1081G. 
  36. ↑ "Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue". The European Journal of Neuroscience 20 (1): 92–100. July 2004. doi:10.1111/j.1460-9568.2004.03459.x. PMID 15245482. 
  37. ↑ "Electroacupuncture - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/medicine-and-dentistry/electroacupuncture. 
  38. ↑ "Understanding endorphins and their importance in pain management". Hawaii Medical Journal 69 (3): 70–71. March 2010. PMID 20397507. 
  39. ↑ "Happiness & Health: The Biological Factors- Systematic Review Article". Iranian Journal of Public Health 43 (11): 1468–1477. November 2014. PMID 26060713. 
  40. ↑ "Social laughter is correlated with an elevated pain threshold". Proceedings. Biological Sciences 279 (1731): 1161–1167. March 2012. doi:10.1098/rspb.2011.1373. PMID 21920973. 
  41. ↑ "The runner's high: opioidergic mechanisms in the human brain". Cerebral Cortex 18 (11): 2523–2531. November 2008. doi:10.1093/cercor/bhn013. PMID 18296435. 
  42. ↑ "Yes, Running Can Make You High". The New York Times. 2008-03-27. ISSN 0362-4331. https://www.nytimes.com/2008/03/27/health/nutrition/27best.html. 
  43. ↑ "Getting to the Bottom of the Runner's High" (in en-US). The New York Times. 2021-03-10. ISSN 0362-4331. https://www.nytimes.com/2021/03/10/well/move/running-exercise-mental-effects.html. 
  44. ↑ "Effects of exercise and physical activity on anxiety". Frontiers in Psychiatry 4: 27. 2013-04-23. doi:10.3389/fpsyt.2013.00027. PMID 23630504. 
  45. ↑ "Clarifying exercise addiction: differential diagnosis, co-occurring disorders, and phases of addiction". International Journal of Environmental Research and Public Health 8 (10): 4069–4081. October 2011. doi:10.3390/ijerph8104069. PMID 22073029. 

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