title: Direct subunit-dependent multimodal 5-hydroxytryptamine3 receptor antagonism by methadone.
abstract: Homomeric 5-hydroxytryptamine (5-HT)(3A) and heteromeric 5-HT(3AB) receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a mu-opioid receptor agonist, is a potent competitive inhibitor of 5-HT(3) receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT(3) receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT(3A) receptors (IC(50) = 14.1 +/- 2.5 microM). Incorporation of the 5-HT(3B) subunit into heteromeric 5-HT(3AB) receptors reduced the potency of inhibition by (R/S)-methadone (IC(50) = 41.1 +/- 0.9 microM). (R/S)-Methadone also increased apparent desensitization of both 5-HT(3) receptor subtypes. The inhibition of the 5-HT(3A) receptor was competitive; however, incorporation of the 5-HT(3B) 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-HT(3AB) 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-HT(3) receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT(3AB) receptors than did (S)-methadone. Inhibition of 5-HT(3A) receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT(3) receptors.
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.forename: Douglas
authors.initials: D
authors.lastname: Sharp
authors.forename: Tim G
authors.initials: TG
authors.lastname: Hales
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008691:Methadone / Q000737:chemistry / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D009020:Morphine; D008691:Methadone