Chemistry:Endorphins

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Endorphins (contracted from "endogenous morphine"[1][2]) are endogenous opioid neuropeptides and peptide hormones in humans and other animals. They are produced and stored in the pituitary gland. The classification of molecules as endorphins is based on their pharmacological activity, as opposed to a specific chemical formulation.

The endorphin class consists of α-endorphin, β-endorphin, and γ-endorphin. All three preferentially bind to μ-opioid receptors.[3] The principal function of endorphins is to inhibit the communication of pain signals. Endorphins may also produce a feeling of euphoria very similar to that produced by other opioids.[4]

History

Opioid peptides in the brain were first discovered in 1974 by two independent groups of investigators:

  • John Hughes and Hans Kosterlitz isolated "enkephalins" (from the Greek εγκέφαλος, cerebrum) from pig brain.[5][6]
  • Rabi Simantov and Solomon H. Snyder isolated morphine-like peptides from calf brain.[7] Eric J. Simon, who independently discovered opioid receptors, would later term these peptides endorphins.[8]

Studies have subsequently distinguished between enkephalins, endorphins, and endogenously produced morphine,[9][10] which is not a peptide.

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.[3] α-endorphin is the smallest, and β-endorphin is the largest.

Name Sequence Reference
α-endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH [11]
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 [12][13]
γ-endorphin Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH [11]

Synthesis

Endorphins are produced in the pituitary gland. All three types of endorphins are fragments of the precursor protein proopiomelanocortin (POMC). POMC is fragmented into many different smaller proteins, including 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.[13][14][15]

Mechanism of action

Endorphins are released from the pituitary gland 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. Endorphin binding at μ-receptors inhibits pain signals in peripheral nerves by blocking the 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, the neurotransmitter associated with pleasure.[12][16]

Functions

Endorphins play a major role in the body's inhibitory response to pain. For example, endorphin release is responsible for producing the euphoric state in cases such as runner's high, sex, orgasm, listening to music, and eating appetizing food such as chocolate.[12][17] Research has demonstrated that meditation by trained individuals can be used to trigger endorphin release.[17] Laughter may also stimulate endorphin production and elevate one's pain threshold.[18]

Endorphin production can also be triggered by vigourous aerobic exercise. β-endorphin release contributes to a phenomenon known as a "runner's high."[19][20] Endorphins may contribute to the positive effect of exercise on anxiety and depression.[21] 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.[22]

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 [117]." 
  3. ↑ 3.0 3.1 Li Y, Lefever MR, Muthu D, Bidlack JM, Bilsky EJ, Polt R (February 2012). "Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins". Future Medicinal Chemistry 4 (2): 205–26. doi:10.4155/fmc.11.195. PMID 22300099. 
  4. ↑ "Is there a link between exercise and happiness?". 2009-06-22. http://science.howstuffworks.com/life/exercise-happiness2.htm. 
  5. ↑ "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. 
  6. ↑ Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR (December 1975). "Identification of two related pentapeptides from the brain with potent opiate agonist activity". Nature 258 (5536): 577–80. doi:10.1038/258577a0. PMID 1207728. Bibcode: 1975Natur.258..577H. 
  7. ↑ Simantov R, Snyder SH (July 1976). "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): 2515–9. doi:10.1073/pnas.73.7.2515. PMID 1065904. Bibcode: 1976PNAS...73.2515S. 
  8. ↑ Goldstein A, Lowery PJ (September 1975). "Effect of the opiate antagonist naloxone on body temperature in rats". Life Sciences 17 (6): 927–31. doi:10.1016/0024-3205(75)90445-2. PMID 1195988. 
  9. ↑ "Endogenous formation of morphine in human cells". Proceedings of the National Academy of Sciences of the United States of America 101 (39): 14091–6. September 2004. doi:10.1073/pnas.0405430101. PMID 15383669. Bibcode: 2004PNAS..10114091P. 
  10. ↑ Kream RM, Stefano GB (October 2006). "De novo biosynthesis of morphine in animal cells: an evidence-based model". Medical Science Monitor 12 (10): RA207-19. PMID 17006413. 
  11. ↑ 11.0 11.1 Ling N, Burgus R, Guillemin R (November 1976). "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): 3942–6. doi:10.1073/pnas.73.11.3942. PMID 1069261. 
  12. ↑ 12.0 12.1 12.2 Chaudhry SR, Bhimji SS (2018). Biochemistry, Endorphin. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK470306/. Retrieved 2019-02-20. 
  13. ↑ 13.0 13.1 "Endorphins: new gut peptides with a familiar face". Gastroenterology 77 (5): 1132–40. November 1979. doi:10.1016/S0016-5085(79)80089-X. PMID 226450. https://www.gastrojournal.org/article/S0016-5085(79)80089-X/pdf. 
  14. ↑ "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): 4719–23. October 1978. doi:10.1073/pnas.75.10.4719. PMID 216997. 
  15. ↑ "Opioid peptides endorphins in pituitary and brain". Science 193 (4258): 1081–6. September 1976. doi:10.1126/science.959823. PMID 959823. Bibcode: 1976Sci...193.1081G. 
  16. ↑ Sprouse-Blum AS, Smith G, Sugai D, Parsa FD (March 2010). "Understanding endorphins and their importance in pain management". Hawaii Medical Journal 69 (3): 70–1. PMID 20397507. 
  17. ↑ 17.0 17.1 Dfarhud D, Malmir M, Khanahmadi M (November 2014). "Happiness & Health: The Biological Factors- Systematic Review Article". Iranian Journal of Public Health 43 (11): 1468–77. PMID 26060713. 
  18. ↑ Dunbar RI, Baron R, Frangou A, Pearce E, van Leeuwen EJ, Stow J, Partridge G, MacDonald I, Barra V, van Vugt M (March 2012). "Social laughter is correlated with an elevated pain threshold". Proceedings: Biological Sciences 279 (1731): 1161–7. doi:10.1098/rspb.2011.1373. PMID 21920973. 
  19. ↑ "The runner's high: opioidergic mechanisms in the human brain". Cerebral Cortex 18 (11): 2523–31. November 2008. doi:10.1093/cercor/bhn013. PMID 18296435. http://mediatum.ub.tum.de/doc/693893/document.pdf. [yes|permanent dead link|dead link}}]
  20. ↑ Kolata, Gina (2008-03-27). "Yes, Running Can Make You High". The New York Times. ISSN 0362-4331. https://www.nytimes.com/2008/03/27/health/nutrition/27best.html. 
  21. ↑ Anderson E, Shivakumar G (2013-04-23). "Effects of exercise and physical activity on anxiety". Frontiers in Psychiatry 4: 27. doi:10.3389/fpsyt.2013.00027. PMID 23630504. 
  22. ↑ Freimuth M, Moniz S, Kim SR (October 2011). "Clarifying exercise addiction: differential diagnosis, co-occurring disorders, and phases of addiction". International Journal of Environmental Research and Public Health 8 (10): 4069–81. doi:10.3390/ijerph8104069. PMID 22073029. 

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