Morphine-induced analgesia in rats withdrawn from concurrent nimodipine and morphine treatment

The effect of repeated administration of dihydropyridine calcium channel an tagonist, nimodipine, given concurrently with morphine on the development o f tolerance to the antinociceptive actions of morphine in rats was studied. In acute experiments nimodipine (1 mg/kg i.p.) enhanced the antinociceptiv e effect of morphine (2.5 mg/kg s.c.) in the hot-plate and tail immersion t eals. Daily administration of morphine either for 10 days (increasing the d aily dose from 20 to 35 mg/kg) or for 24 days (increasing the daily dose fr om 20 to 70 mg/kg) induced tolerance to the antinociceptive effect of a cha llenge dose of morphine (10 mg/kg) administered 24 h after the withdrawal f rom chronic morphine. Concurrent administration of nimodipine (1 mg/kg per day) with morphine for 10 or 24 days augmented the reduction of the antinoc iceptive effect of morphine. Neither acute nor repeated administration of n imodipine with morphine altered the concentrations of morphine or its metab olite morphine 6-glucuronide in the brain tissue or in the plasma. The obse rved further reduction in the nociceptive response in morphine tolerant ani mals pre-treated with nimodipine is, most probably, due to the adaptive cha nges in the central dihydropyridine calcium channels induced by the withdra wal from repeated nimodipine treatment. (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.