Editing Methadone (section)

=== Mechanism of action ===
[[Levomethadone]] (the ''R''-(–)-methadone enantiomer) is a [[μ-opioid receptor]] agonist with higher [[intrinsic activity]] than morphine, but lower affinity.<ref>{{cite book| veditors = Davis MP, Glare P, Hardy JR, Columba Q |title= Opioids in Cancer Pain|date=2009|publisher=Oxford University Press|location=Oxford, UK|isbn=978-0-19-923664-0|edition=2nd|pages=211–212}}</ref> [[Dextromethadone]] (the ''S''-(+)-methadone enantiomer) has a much lower affinity to the μ-opioid receptor than levomethadone. Both enantiomers bind to the [[glutamatergic]] [[NMDA]] (''N''-methyl-{{Small|D}}-aspartate) receptor, acting as noncompetitive antagonists. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism.{{Citation needed|date=December 2022}} NMDA antagonists such as [[dextromethorphan]], [[ketamine]], [[tiletamine]] and [[ibogaine]] are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal,{{Citation needed|date=December 2022}} possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain.{{Citation needed|date=May 2024}} Methadone also acted as a potent, [[noncompetitive]] [[alpha-3 beta-4 nicotinic receptor|α<sub>3</sub>β<sub>4</sub>]] neuronal [[nicotinic acetylcholine receptor]] [[nicotinic antagonist|antagonist]] in rat receptors, expressed in human embryonic kidney cell lines.<ref>{{cite journal | vauthors = Xiao Y, Smith RD, Caruso FS, Kellar KJ | title = Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 366–371 | date = October 2001 | doi = 10.1016/S0022-3565(24)29338-1 | pmid = 11561100 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11561100 | access-date = 21 June 2011 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828170410/https://jpet.aspetjournals.org/content/299/1/366.long | url-status = dead }}</ref>