On the mechanism of cross-tolerance between morphine- and nicotine-induced antinociception: involvement of calcium channels.

The present study focused on the evaluation of a mechanism of nicotine-induced antinociception and cross-tolerance to antinociceptive effects between nicotine and morphine in mice. The results indicate that, at a dose of 3 mg/kg, nicotine produced a significant antinociception in the hot-plate test. Additionally, the L-type voltage-dependent calcium channel antagonists, nimodipine, verapamil and diltiazem (5, 10 and 20 mg/kg), as well as an opioid receptor antagonist naloxone (0.5 and 1 mg/kg), dose-dependently attenuated this nicotine-induced antinociception. In a second series of experiments, mice were treated with morphine (25 and 50 mg/kg) once daily, for 3 days. On the 4th day, the antinociceptive response of morphine (10 mg/kg) and nicotine (3 mg/kg) was measured. Tolerance to the effects of both drugs was observed only in mice pretreated with the highest dose of morphine. Furthermore, the administration of nimodipine, diltiazem, flunarizine (10 and 20 mg/kg), but not of verapamil (10 and 20 mg/kg) nor mecamylamine (1 and 2 mg/kg) prior to morphine injections, prevented this cross-tolerance to the antinociceptive effects of morphine and nicotine. These findings support the hypothesis that similar opioid- and calcium-dependent mechanisms are involved in morphine- and nicotine-induced antinociception and in the development of cross-tolerance between these drugs.