Direct subunit-dependent multimodal 5-hydroxytryptamine(3) receptor antagonism by methadone

Tarek Z. Deeb, Douglas Sharp, Tim G. Hales (Lead / Corresponding author)

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    13 Citations (Scopus)

    Abstract

    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 mu-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 mu M). 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 mu M). (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.

    Original languageEnglish
    Pages (from-to)908-917
    Number of pages10
    JournalMolecular Pharmacology
    Volume75
    Issue number4
    DOIs
    Publication statusPublished - Apr 2009

    Keywords

    • N1E-115 NEUROBLASTOMA-CELLS
    • HUMAN 5-HT3A RECEPTORS
    • TYPE-3 RECEPTORS
    • MOLECULAR DETERMINANTS
    • ONDANSETRON
    • INHIBITION
    • CHANNEL
    • CNS
    • ACTIVATION
    • BLOCKADE

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