Effects of dextrorotatory morphinans on brain Na+ channels expressed in Xenopus oocytes

We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects. 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 Na+ channel activity. We used the two-microelectrode voltage-clamp technique to test the effects of DM, DF, AM, CM and HM on Na+ currents (INa) in Xenopus oocytes expressing cRNAs encoding rat brain Nav1.2 α and β1 or β2 subunits. In oocytes expressing Na+ channels, DM, DF, AM and CM, but not HM, induced tonic and use-dependent inhibitions of peak INa following low- and high-frequency stimulations. The order of potency for the inhibition of peak INa was AM − CM > DM = DF. The DM, DF, AM and CM-induced tonic inhibitions of peak INa were voltage-dependent, dose-dependent and reversible. The IC50 values for DM, DF, AM and CM were 116.7 ± 14.9, 175.8 ± 16.9, 38.6 ± 15.5, and 42.5 ± 8.5 μM, respectively. DM and its analogs did not affect the steady-state activation and inactivation voltages. AM and CM, but not DM and DF, inhibited the plateau INa more effectively than the peak INa in oocytes expressing inactivation-deficient I1485Q–F1486Q–M1487Q (IFMQ3) mutant channels; the IC50 values for AM and CM in this system were 8.4 ± 1.3 and 8.7 ± 1.3 μM, respectively, for the plateau INa and 43.7 ± 5.9 and 32.6 ± 7.8 μM, respectively, for the peak INa. These results collectively indicate that DM and its analogs could be novel Na+ channel blockers acting on the resting and open states of brain Na+ channels.