Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine₃Receptor 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 -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 ϭ 14.1 Ϯ 2.5 M). Incorporation of the 5-HT 3B subunit into heteromeric 5-HT 3AB receptors reduced the potency of inhibition by (R/S)-methadone (IC 50 ϭ 41.1 Ϯ 0.9 M). (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.The 5-hydroxytryptamine (5-HT) type 3 receptor is a ligand-gated cation channel that mediates rapid serotonergic excitatory synaptic transmission (Sugita et al., 1992). It contains binding sites for 5-HT and several allosteric modulators. The 5-HT 3 receptor is a member of the Cys-loop superfamily of pentameric receptors, which also includes the nicotinic acetylcholine, ␥-aminobutyric acid, and glycine receptors, and the Zn 2ϩ -activated ion channel (Barnes et al., 2009). The 5-HT 3A subunit forms homomeric receptors and can also combine into heteromeric receptors with the 5-HT 3B

Hepatitis C Virus Infection Influences the S-Methadone Metabolite Plasma Concentration

“…R -methadone thus seems to be the major stereoisomer involved in pain relief and the prevention of opioid withdrawal. S -methadone (or d -isomer) is an antagonist of the NMDA receptor [27] and also inhibits the reuptake of 5-hydroxytryptamine [28]. S -methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmia [29].…”

Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site

“…In another study Das and Dillon (2005) using murine receptors reported an ∼40 fold difference in the IC 50 values of PTX (5-HT 3 A, 41 μM; 5-HT 3 AB, 1.1 mM), and also showed that an M2 residue (6′) was a common determinant of PTX inhibition. Thus, while it is possible that the difference in potency is due to different behaviours at these two subtypes, as, for example, has been described for methadone (Deeb et al., 2009), we speculate that the mechanisms of action of the structurally-related gingkolide compounds are similar in homomeric and heteromeric receptors, and it is the different pore lining residues that are the cause of the different potencies.…”

Allosteric modulation of the 5-HT3 receptor

“…Methadone, an opioid often used to treat morphine addiction, also competitively inhibits human 5-HT 3 A receptors and increases desensitization. However, an insurmountable block was observed for heteromeric human 5-HT 3 AB receptors [34*]. …”