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Biochemistry, Endorphin

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Last Update: April 3, 2023.


Endogenous morphine, coined by the morphing of the two descriptive terms into endorphins, are opioid neuropeptides that are naturally produced in the body that serve a primary function as an agent blocking the perception of pain and, additionally, present in cases of pleasure. Historically, morphine receptors were discovered in the nervous system before the discovery and understanding of endorphins. This natural receptor spoke to the possibility of the existence and effect of endorphins that was later confirmed.

Endorphins were discovered to not only display functions as neurotransmitters in the central nervous system but additionally as peptide hormones released into the circulatory system by the pituitary gland. Endorphins have been linked clinically to cases of mental issues, including autism, depression, and depersonalization disorder, as well as to activities such as laughter and vigorous aerobic exercise.[1][2][3]

Molecular Level

The origins of endorphins have been traced to the precursor pro-opiomelanocortin (POMC) polypeptide, which is synthesized in the pituitary gland. Recent studies have produced evidence suggesting that POMC may also be produced by the immune system and, consequently, also provide a base source for endorphin production. POMC consists of a 241 amino acid chain which is cleaved by enzyme (prohormone convertases) action into the 93 amino acid single-chain polypeptide beta-lipoprotein (beta-LPH). Beta-LPH is cleaved via enzymes into beta-melanocyte-stimulating hormone and endorphins, amongst other molecule types. Endorphins are identified as three distinct peptides termed alpha-endorphins, beta-endorphins, and gamma-endorphins. The beta-endorphins are the longest chain, containing 31 amino acids in the following sequence: 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. This sequence corresponds to amino acids 104 to 134 in the sequence of beta-LPH. The second-longest chain is the gamma-endorphins, consisting of a 17 amino acid chain the same as the first 17 amino acid chain sequence of the beta-endorphins. Finally, the third and shortest type of endorphins about the amino acid chain sequence is the alpha-endorphins. The alpha-endorphins are amino acid chains comprised of the same first 16 amino acid sequence as the beta-endorphins (and consequently has the same sequence of the first 16 amino acids comprising the gamma-endorphins). Thus, the sequences of beta-endorphins and gamma-endorphins essentially have the sequence of alpha-endorphins nested within them. This molecular configuration thereby allows these endorphins to be the agonist of opioid receptors, the same receptors to which chemicals derived from opium, such as morphine, bind to for triggering physiological responses.[4][5][6]


The function of endorphins can be stated in general terms as well as broken down specifically and observed per each endorphin type. In general, the release of endorphins is understood to be associated with the body’s response to pain. The pain relief experienced as a result of the release of endorphins has been determined to be greater than that of morphine. β-endorphin (an endogenous opioid) is one of the neurochemicals involved with exercise-induced euphoria (runner's high). Additionally, endorphins have been found to be associated with states of pleasure, including such emotions brought upon by laughter, love, sex, and even appetizing food. Of the three endorphin types, beta-endorphins have been the most studied and prevalent, accounting for the majority of the functional properties of endorphins as generalized and understood as a whole. Research is ongoing on each type to further understand the full functional potential of each, along with how they can be used in a medically beneficial manner. Endorphins express functional duality as they fall into the category of either neurotransmitters or neuromodulators in the central nervous system (CNS) and hormones in the pituitary gland.[7][8]


The mechanism of endorphins can be viewed through two different lenses through activity in the peripheral nervous system (PNS) and the CNS. In the PNS, the perception of pain relief is produced beta-endorphins bind to opioid receptors. Opioid receptors are broken down into four primary classes of G protein-coupled receptors: mu-receptors, delta-receptors, kappa-receptors, and nociceptin receptors. The greatest binding potential exists between the beta-endorphins and the mu-receptors. Mu-receptors can be found throughout the nerves of the PNS. When this beta-endorphin to mu-receptor binding occurs on nerve terminals (happening pre-synaptically or post-synaptically), analgesic effects are realized. The effects are realized as the aforementioned binding results in triggering of chemical events preventing the release of substance P, amongst other tachykinins, which is an instrumental undecapeptide in the conveyance of pain. Just as beta-endorphin to mu-opioid binding occurs in the peripheral nervous system, it also occurs in the central nervous system. There is a difference, though, as the mechanism triggered by the binding opposes the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) as opposed to substance P. With this suppression of GABA, the result is an increase in production and action of dopamine, the pleasure, and reward-associated neurotransmitter.

Clinical Significance

From a clinical standpoint, endorphins and their effects and interactions are still being understood and studied. One basic yet noteworthy interaction of endorphins is with naloxone. Naloxone is administered as a drug, typically in the case of opioid overdose, to mitigate bodily response to the opioid. This is achieved by binding to the opioid receptors, making it not only difficult for opioid binding but also endorphin binding, and thereby reducing the effect of available endorphins. Studies have been conducted in relation to naloxone usage in the presence of depersonalization disorder, and it was found that patient conditions improved. Based on this, endorphins are suspected of being linked with contributing to this disorder. Another interaction of clinical significance includes cases where the patient has a physical dependence on an opiate. Links have been made to opiate dependence and hypothalamo-hypophyseal-gonadal dysfunction. Studies have supported beta-endorphins as affecting the pituitary gland’s release of luteinizing hormone through gonadotropin-releasing hormone influence and thereby as being involved with gonadal homeostasis. Thus, the association is made between the effects of opiate dependency on gonadal homeostasis via the interruption of effective beta-endorphin action. An interesting correlation also has been made about the administration of opioid medications versus non-opioid pain medication prescribed for patients following surgery. Levels of beta-endorphins were found to be high in patients using opioid medications, correlating to a physiological response to pain. However, it was interesting to note that in the presence of rofecoxib (a COX-2 inhibitor), beta-endorphin levels remain unaffected as opposed to in the presence of acetaminophen, where beta-endorphin levels declined with its use. The rofecoxib resulted in a less perceived feeling of pain, potentially attributed to the maintenance of the beta-endorphin levels, but exactly in what way this interaction allowed for this is still being understood. The result of such a deeper understanding would be to exploit that knowledge to use more effective non-opioid pain reducers that lack the negative properties of opioids, such as addiction and tolerance over prolonged usage.[9][10]

Review Questions


Adeodu OO, Olorunmoteni OE, Oseni SBA, Obuotor EM. Plasma and Cerebrospinal Fluid Beta-Endorphin Levels Show a Strong Association in Children with Cerebral Malaria. J Pediatr Neurosci. 2018 Oct-Dec;13(4):416-422. [PMC free article: PMC6413603] [PubMed: 30937082]
Shenoy SS, Lui F. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 20, 2022. Biochemistry, Endogenous Opioids. [PubMed: 30422494]
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Yoo JH, Kitchen I, Bailey A. The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us? Br J Pharmacol. 2012 Aug;166(7):1993-2014. [PMC free article: PMC3402766] [PubMed: 22428846]
Rodriguez FD, Coveñas R. Targeting opioid and neurokinin-1 receptors to treat alcoholism. Curr Med Chem. 2011;18(28):4321-34. [PubMed: 21861818]
Gentilucci L, Tolomelli A, Squassabia F. Peptides and peptidomimetics in medicine, surgery and biotechnology. Curr Med Chem. 2006;13(20):2449-66. [PubMed: 16918365]

Disclosure: Shazia Chaudhry declares no relevant financial relationships with ineligible companies.

Disclosure: William Gossman declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

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Bookshelf ID: NBK470306PMID: 29262177


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