Influence of ATP-dependent K+ channels on nicotine-induced inhibition of withdrawal in morphine-dependent mice

In the present study, we have investigated the effect of nicotine and diazoxide, a potassium channel opener and glibenclamide, a potassium channel (KATP) blocker on naloxone-precipitated physical withdrawal signs, including jumping and diarrhea. Then, the interactions of nicotine with diazoxide and glibenclamide were tested. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulphate 3 times a day for 3 days, and jumping behavior and diarrhea were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulphate on day 4. Nicotine was administered 15 min and diazoxide and glibenclamide 30 min before naloxone injection. Nicotine (0.01-1 mg/kg, s.c.) and (0.1-1 mg/kg) reduced withdrawal jumping and diarrhea respectively. Diazoxide (8-64 mg/kg, i.p.) decreased jumping behavior significantly, but had no significant effect on diarrhea. On the other hand glibenclamide (0.25-1 mg/kg i.p.) and (1 mg/kg) augmented jumping and diarrhea respectively. The response of nicotine on jumping or on diarrhea was potentiated by diazoxide and decreased by glibenclamide pretreatment. The isobolographic analysis revealed synergistic interaction between diazoxide and nicotine on decreasing physical withdrawal signs including jumping and diarrhea in morphine-dependent mice. According to these results the interaction of nicotine with the KATP channel opener and blocker in morphine physical withdrawal signs could be explained by direct and indirect effects of nicotine on membrane potassium currents.