Methadone is a Non‐Competitive Antagonist at the α4β2 and α3* Nicotinic Acetylcholine Receptors and an Agonist at the α7 Nicotinic Acetylcholine Receptor. (7th October 2014)

• Record Type: Journal Article
• Authors: Talka, Reeta; Salminen, Outi; Tuominen, Raimo K.
• Is Part Of: Basic & clinical pharmacology & toxicology. Volume 116:Number 4(2015:Apr.)
• Page Start: 321
• Page End: 328
• Publication Date: 2014-10-07
• Subjects: Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology, Clinical -- Periodicals; Computer network resources; Electronic journals; 615.1
• DOI: 10.1111/bcpt.12317
• Languages: English
• ISSNs: 1742-7835

Abstract

<abstract abstract-type="main" id="bcpt12317-abs-0001"> <title>Abstract</title> <p>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 <italic>in vitro</italic> studies have shown that methadone is a non‐competitive antagonist at rat α3β4 nicotinic acetylcholine receptors (nAChR) and an agonist at human α7 nAChRs. In this study, we used cell lines expressing human α4β2, α7 and α3* nAChRs to compare the interactions of methadone at the various human nAChRs under the same experimental conditions. A [<sup>3</sup>H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and <sup>86</sup>Rb<sup>+</sup> efflux and changes in intracellular calcium [Ca<sup>2+</sup>]<sub>i</sub> were used to assess changes in the functional activity of the receptors. Methadone displaced [<sup>3</sup>H]epibatidine from nicotinic agonist‐binding sites in SH‐EP1‐hα7 and SH‐SY5Y cells, but not in SH‐EP1‐hα4β2 cells. The <italic>K</italic><sub><italic>i</italic></sub> values for methadone were 6.3 μM in SH‐EP1‐hα7 cells and 19.4 μM and 1008 μM in SH‐SY5Y cells. Methadone increased [Ca<sup>2+</sup>]<sub>i</sub> in all cell lines in a concentration‐dependent manner, and in SH‐EP1‐hα7 cells, the effect was more pronounced than the effect of nicotine treatment. In SH‐EP1‐hα4β2 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre‐treatment abolished the nicotine‐induced response in [Ca<sup>2+</sup>]<sub>i</sub> in all cell lines expressing nAChRs. In SH‐EP1‐hα4β2 and SH‐SY5Y cells, methadone had no effect on the <sup>86</sup>Rb<sup>+</sup> efflux, but it antagonized the nicotine‐induced <sup>86</sup>Rb<sup>+</sup> ion efflux in a non‐competitive manner. These results suggest that methadone is an agonist at human α7 nAChRs and a non‐competitive antagonist at human α4β2 and α3* 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.</p> </abstract>