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

Abstract

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-methylmotphinan; 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 (I-Na) in Xenopus oocytes expressing cRNAs encoding rat brain Nav1.2 alpha and beta 1 or beta 2 subunits. In oocytes expressing Na+ channels, DM, DF, AM and CM, but not HM, induced tonic and use-dependent inhibitions of peak I-Na following low- and high-frequency stimulations. The order of potency for the inhibition of peak I-Na was AM - CM > DM = DF. The DM, DF, AM and CM-induced tonic inhibitions of peak IN, 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 mu M, 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 IN, more effectively than the peak IN, in oocytes expressing inactivation-deficient 11485Q-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 mu M, respectively, for the plateau I-Na and 43.7 +/- 5.9 and 32.6 +/- 7.8 mu M, respectively, for the peak I-Na. Theseresults collectively indicate that DM and its analogs could be novel Na+ channel blockers acting on the resting and open states of brain Na+ channels. (c) 2007 Elsevier B.V All rights reserved.