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 language | English |
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Pages (from-to) | 908-917 |
Number of pages | 10 |
Journal | Molecular Pharmacology |
Volume | 75 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2009 |
Keywords
- N1E-115 NEUROBLASTOMA-CELLS
- HUMAN 5-HT3A RECEPTORS
- TYPE-3 RECEPTORS
- MOLECULAR DETERMINANTS
- ONDANSETRON
- INHIBITION
- CHANNEL
- CNS
- ACTIVATION
- BLOCKADE