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Endorphins 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, and inhibit pain, muscle cramps, and relieve stress.
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.
beta-Endorphin (β-endorphin) is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.
Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.
Solomon Halbert Snyder is an American neuroscientist who has made wide-ranging contributions to neuropharmacology and neurochemistry. He studied at Georgetown University, and has conducted the majority of his research at the Johns Hopkins School of Medicine. Many advances in molecular neuroscience have stemmed from Snyder's identification of receptors for neurotransmitters and drugs, and elucidation of the actions of psychotropic agents. He received the Albert Lasker Award for Basic Medical Research in 1978 for his research on the opioid receptor, and is one of the most highly cited researchers in the biological and biomedical sciences, with the highest h-index in those fields for the years 1983–2002, and then from 2007–2019.
Hans Walter Kosterlitz FRS was a German-born British biochemist.
Endomorphins are considered to be natural opioid neurotransmitters central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.
Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids.
The ∆-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the ∆-opioid receptor is largely expressed vary from species model to species model. In humans, the ∆-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.
Naltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research. In May 2012 a paper was published in Nature with the structure of naltrindole in complex with the mouse δ-opioid G-protein coupled receptor, solved by X-ray crystallography.
Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter. It has little to no effect on the κ-opioid receptor.
DAMGO is a synthetic opioid peptide with high μ-opioid receptor specificity. It was synthesized as a biologically stable analog of δ-opioid receptor-preferring endogenous opioids, leu- and met-enkephalin. Structures of DAMGO bound to the µ opioid receptor reveal a very similar binding pose to morphinans.
RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.
Spinorphin is an endogenous, non-classical opioid peptide of the hemorphin family first isolated from the bovine spinal cord (hence the prefix spin-) and acts as a regulator of the enkephalinases, a class of enzymes that break down endogenous the enkephalin peptides. It does so by inhibiting the enzymes aminopeptidase N (APN), dipeptidyl peptidase III (DPP3), angiotensin-converting enzyme (ACE), and neutral endopeptidase (NEP). Spinorphin is a heptapeptide and has the amino acid sequence Leu-Val-Val-Tyr-Pro-Trp-Thr (LVVYPWT). It has been observed to possess antinociceptive, antiallodynic, and anti-inflammatory properties. The mechanism of action of spinorphin has not been fully elucidated (i.e., how it acts to inhibit the enkephalinases), but it has been found to act as an antagonist of the P2X3 receptor, and as a weak partial agonist/antagonist of the FP1 receptor.
Hemorphin-4 is an endogenous opioid peptide of the hemorphin family which possesses antinociceptive properties and is derived from the β-chain of hemoglobin in the bloodstream. It is a tetrapeptide with the amino acid sequence Tyr-Pro-Trp-Thr. Hemorphin-4 has affinities for the μ-, δ-, and κ-opioid receptors that are in the same range as the structurally related β-casomorphins, although affinity to the κ-opioid receptor is markedly higher in comparison. It acts as an agonist at these sites. Hemorphin-4 also has inhibitory effects on angiotensin-converting enzyme (ACE), and as a result, may play a role in the regulation of blood pressure. Notably, inhibition of ACE also reduces enkephalin catabolism.
Hemorphins are a class of naturally occurring, endogenous opioid peptides which are found in the bloodstream, and are derived from the β-chain of hemoglobin. They have antinociceptive effects via activation of the opioid receptors, and some may also play a role in blood pressure through inhibition of the angiotensin-converting enzyme (ACE), as well as cause an elevation of endogenous enkephalin levels. Some examples of hemorphins include hemorphin-4, spinorphin, and valorphin.
Metkefamide (INN; LY-127,623), or metkephamid acetate (USAN), but most frequently referred to simply as metkephamid, is a synthetic opioid pentapeptide and derivative of [Met]enkephalin with the amino acid sequence Tyr-D-Ala-Gly-Phe-(N-Me)-Met-NH2. It behaves as a potent agonist of the δ- and μ-opioid receptors with roughly equipotent affinity, and also has similarly high affinity as well as subtype-selectivity for the κ3-opioid receptor.
Graeme Henderson is a British neuroscientist whose research focuses on opioid addiction. He is professor of pharmacology in the School of Physiology, Pharmacology and Neuroscience, University of Bristol.
References
- 1 2 Hughes, Prof. John, Who's Who 2018, A & C Black, 2017
- ↑ Marshall, Fiona (1990). Cholecystokinin/dopamine interactions in the rat basal ganglia (PhD thesis). University of Cambridge. EThOS uk.bl.ethos.386170.
- 1 2 3 4 5 "Professor John Hughes". Wolfson College, University of Cambridge. Retrieved 8 January 2017.
- 1 2 "John Hughes: Biography". The Royal Society. Retrieved 23 January 2017.
- 1 2 "Opiate receptors and enkephalins". Lasker Foundation. Retrieved 8 January 2017.
- 1 2 3 4 5 Goldberg, Jeff (2013). Anatomy of a Scientific Discovery: The Race to Find the Body's Own Morphine. Skyhorse Publishing. ISBN 9781626361935.
- 1 2 Freeman, Karen (8 November 1996). "Hans W. Kosterlitz, 93; Found Clues in Brain on Pain Control". The New York Times.
- 1 2 Snyder, Solomon H. (1988). "Initial Findings". In Pasternak, Gavril (ed.). The Opiate Receptors. Humana Press. p. 4. ISBN 9781607619925.
- 1 2 3 4 Frankenburg, Frances R. (2014). Brain-Robbers: How Alcohol, Cocaine, Nicotine, and Opiates Have Changed Human History. Praeger. p. 213. ISBN 9781440829314.
- ↑ Tansey, E.M.; Christie, D.A., eds. (7 November 1995). 3. Endogenous Opiates. Wellcome Witnesses to Twentieth Century Medicine. Wellcome Trust. p. 73. ISBN 9781869835798.
- ↑ Hughes, J.; Smith, T.W.; Kosterlitiz, H.W.; Fothergill, Linda A.; Morgan, B.A.; Morris, H.R. (18 December 1975). "Identification of two related pentapeptides from the brain with potent opiate agonist activity". Nature. 258 (5536): 577–579. Bibcode:1975Natur.258..577H. doi:10.1038/258577a0. PMID 1207728. S2CID 95411.
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