RT Journal Article SR Electronic T1 Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine3 Receptor Antagonism by Methadone JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 908 OP 917 DO 10.1124/mol.108.053322 VO 75 IS 4 A1 Tarek Z. Deeb A1 Douglas Sharp A1 Tim G. Hales YR 2009 UL http://molpharm.aspetjournals.org/content/75/4/908.abstract AB Homomeric 5-hydroxytryptamine (5-HT)3A and heteromeric 5-HT3AB receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a μ-opioid receptor agonist, is a potent competitive inhibitor of 5-HT3 receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT3 receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT3A receptors (IC50 = 14.1 ± 2.5 μM). Incorporation of the 5-HT3B subunit into heteromeric 5-HT3AB receptors reduced the potency of inhibition by (R/S)-methadone (IC50 = 41.1 ± 0.9 μM). (R/S)-Methadone also increased apparent desensitization of both 5-HT3 receptor subtypes. The inhibition of the 5-HT3A receptor was competitive; however, incorporation of the 5-HT3B subunit caused the appearance of inhibition that was insurmountable by 5-HT. In the absence of rapid desensitization, when dopamine was used as an agonist of 5-HT3AB receptors, the inhibition by (R/S)-methadone was voltage-dependent. The antagonist and desensitization-enhancing effects of (R/S)-methadone were shared by pure (R)- and (S)-methadone enantiomers, which had similar actions on 5-HT-evoked currents mediated by 5-HT3 receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT3AB receptors than did (S)-methadone. Inhibition of 5-HT3A receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT3 receptors. The American Society for Pharmacology and Experimental Therapeutics