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: Tarek Z Deeb, Douglas Sharp, Tim G Hales
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 75 Issue 4 Pg. 908-17 (Apr 2009) ISSN: 1521-0111 [Electronic] United States
• PMID: 19131665 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Protein Subunits
• Receptors, Serotonin, 5-HT3
• Serotonin 5-HT3 Receptor Antagonists
• Serotonin Antagonists
• Morphine
• Methadone

Topics

• Cell Line
• Dose-Response Relationship, Drug
• Humans
• Methadone (chemistry, pharmacology)
• Morphine (pharmacology)
• Protein Subunits (antagonists & inhibitors, physiology)
• Receptors, Serotonin, 5-HT3 (physiology)
• Serotonin 5-HT3 Receptor Antagonists
• Serotonin Antagonists (chemistry, pharmacology)
• Stereoisomerism