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Pathway Description
Methadone Opioid Agonist Action Pathway
Homo sapiens
Drug Action Pathway
Methadone is a synthetic mu-opioid receptor agonst as well as a N-methyl-d-aspartate (NMDA) receptor antagonist. As a mu opioid receptor agonist it exerts similar qualities to other opioids like morphine and heroin by decreasing GABA release from presynatic neurons leading to the disinhibition of dopamine neurons in the spinal chord. This causes analgesia effects promoting pain relief. Methadone by antagonizing NMDA receptors on the post synaptic membrane leads to less calcium influx through the receptor subunits. This also leads to slower depolarization of the neurons in the central nervous system dampening the pain pathway. Due to it's NMDA antagonism it has improved analgesic effect and opioid tolerance. Since it is similar to morphine and other opioids it also has similar risks with addiction, respiratory depression and constipation. Methadone is used as an addiction treatment because of its long duration of action and half life. It's long duration of action makes it ideal for Opioid Agonist Treatment (OAT) or Opioid Substitution Therapy (OST). OAT and OST is the substitution of illicit opioids with the long-acting opioids to prevent withdrawal symptoms for 24-36 hours which ultimately reduce cravings and drug-seeking behaviours leading to the patient less like to seek illicit opioid drug usage.
References
Methadone Opioid Agonist Pathway References
Ferrari A, Coccia CP, Bertolini A, Sternieri E: Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004 Dec;50(6):551-9. doi: 10.1016/j.phrs.2004.05.002.
Pubmed: 15501692
Kapur BM, Hutson JR, Chibber T, Luk A, Selby P: Methadone: a review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci. 2011 Jul-Aug;48(4):171-95. doi: 10.3109/10408363.2011.620601.
Pubmed: 22035341
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. doi: 10.1038/nrd2199.
Pubmed: 17139284
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. doi: 10.1038/nrd2132.
Pubmed: 17016423
Kakko J, von Wachenfeldt J, Svanborg KD, Lidstrom J, Barr CS, Heilig M: Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence. Biol Psychiatry. 2008 Jan 15;63(2):172-7. doi: 10.1016/j.biopsych.2007.05.001. Epub 2007 Sep 11.
Pubmed: 17850768
Kvam TM, Baar C, Rakvag TT, Kaasa S, Krokan HE, Skorpen F: Genetic analysis of the murine mu opioid receptor: increased complexity of Oprm gene splicing. J Mol Med (Berl). 2004 Apr;82(4):250-5. doi: 10.1007/s00109-003-0514-z. Epub 2004 Jan 9.
Pubmed: 14991152
Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11.
Pubmed: 19717013
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