Effects of dextrorotatory morphinans on α3β4 nicotinic acetylcholine receptors expressed in Xenopus oocytes

We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects, and a recent report showed that DM reduces the adverse effects of morphine and blocks α₃β₄ nicotinic acetylcholine receptors, a major target of anti-addictive agents. Here, we investigated the effects of DM, three of its analogs (DF, 3-methyl-17-methylmorphinan; AM, 3-allyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on neuronal α₃β₄ nicotinic acetylcholine receptor channel activity expressed in Xenopus laevis oocytes, using the two-microelectrode voltage clamp technique. We found that intraoocyte injection of neuronal α3 and β4 nicotinic acetylcholine receptor subunit cRNAs elicited an inward current (I_ACh) in the presence of acetylcholine. Co-treatment with DM, DF, AM, CM or HM inhibited I_ACh in a dose-dependent, voltage-independent and reversible manner. The IC₅₀ values for DM, DF, AM, CM and HM were 19.5 ± 5.2, 15.8 ± 4.5, 16.3 ± 1.7, 10.1 ± 2.8, and 13.5 ± 4.0 μM, respectively. The order of potency for the inhibition of I_ACh was CM > HM > DF = AM > DM in oocytes expressing α3β4 nicotinic acetylcholine receptors. The inhibitions of (I_ACh) by DM, DF and HM, AM and CM were non-competitive. These results indicate that AM, CM and HM could be novel non-competitive agents regulating α₃β₄ nicotinic acetylcholine receptor channel activity.