Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor.
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Talka R, Salminen O, Tuominen RK
Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor.
Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7.
- PubMed ID
- 25196810 [ View in PubMed]
- Abstract
Nicotine-methadone interactions have been studied in human beings and in various experimental settings regarding addiction, reward and pain. Most methadone maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous in vitro studies have shown that methadone is a non-competitive antagonist at rat alpha3beta4 nicotinic acetylcholine receptors (nAChR) and an agonist at human alpha7 nAChRs. In this study, we used cell lines expressing human alpha4beta2, alpha7 and alpha3* nAChRs to compare the interactions of methadone at the various human nAChRs under the same experimental conditions. A [(3) H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and (86) Rb(+) efflux and changes in intracellular calcium [Ca(2+) ]i were used to assess changes in the functional activity of the receptors. Methadone displaced [(3) H]epibatidine from nicotinic agonist-binding sites in SH-EP1-halpha7 and SH-SY5Y cells, but not in SH-EP1-halpha4beta2 cells. The Ki values for methadone were 6.3 muM in SH-EP1-halpha7 cells and 19.4 muM and 1008 muM in SH-SY5Y cells. Methadone increased [Ca(2+) ]i in all cell lines in a concentration-dependent manner, and in SH-EP1-halpha7 cells, the effect was more pronounced than the effect of nicotine treatment. In SH-EP1-halpha4beta2 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre-treatment abolished the nicotine-induced response in [Ca(2+) ]i in all cell lines expressing nAChRs. In SH-EP1-halpha4beta2 and SH-SY5Y cells, methadone had no effect on the (86) Rb(+) efflux, but it antagonized the nicotine-induced (86) Rb(+) ion efflux in a non-competitive manner. These results suggest that methadone is an agonist at human alpha7 nAChRs and a non-competitive antagonist at human alpha4beta2 and alpha3* nAChRs. This study adds further support to the previous findings that opioids interact with nAChRs, which may underlie their frequent co-administration in human beings and might be of interest to the field of drug discovery.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Methadone Neuronal acetylcholine receptor subunit alpha-3 Protein Humans UnknownAntagonistDetails Methadone Neuronal acetylcholine receptor subunit alpha-4 Protein Humans UnknownAntagonistDetails Methadone Neuronal acetylcholine receptor subunit alpha-7 Protein Humans YesAgonistDetails Methadone Neuronal acetylcholine receptor subunit beta-2 Protein Humans UnknownAntagonistDetails