The effect of opioid agonist U50488H on Na+ currents was examined in freshly dissociated hippocampal neurons of mice using the whole-cell patch clamp technique. U50488H(1-100 mu M) caused a concentration dependent reversible inhibition of the voltage-activated sodium currents. IC50 of 15.5 mu M and Hill constant of 1.4 were calculated respectively. The inhibitory actions of U50488H on I-Na were still observed in the presence of 30 mu M naloxone. Moreover, under the action of U50488H, repetitive stimulation induced further inhibition which was frequency-dependent. The activation curve did not change before and after application of 10 mu M U50488H. However, after exposure to 10 mu M U50488H and repetitive depolarizing at 10 Hz, frequency-dependent inhibition occurred, and a mean shift of half-activation membrane potential by +20 mV could be induced. The inactivation curve was significantly changed toward negative membrane potential with 10 mu M U50488H, and further negative shift was observed after repetitive depolarizing at 10 Hz. Our results indicate that U50488H could directly inhibit neuronal Na+ currents without involvement in the activation of K-opioid receptors. (C) 2000 Published by Elsevier Science B.V. All rights reserved.