Inhibitory effect of low-dose pentazocine on the development of antinociceptive tolerance to morphine

Purpose. The development of antinociceptive tolerance to morphine is one of the major problems in its clinical use. Therefore, exploring effective measures to prevent morphine tolerance is of great clinical relevance. We evaluated whether pentazocine could prevent morphine tolerance in mice. Methods. Five groups of male ICR mice received repeated subcutaneous (s.c.) injections of morphine at a high dose (10 mg . kg(-1)) or saline, concomitantly with s.c. injections of pentazocine at low, subanalgesic doses (0.1, 0.3, or 1.0 mg . kg(-1)) or saline, respectively, once daily for 14 days. On day 15, mice received co-injections of morphine and pentazocine 120 min after pretreatment with nor-binaltorphimine (5 mg . kg(-1)), a selective kappa-opioid receptor antagonist. The tail pressure threshold was measured before and 60 min after the daily drug co-injections. Results. Repeated s.c. co-injections of morphine and saline resulted in a progressive decrease in morphine-induced anti-nociception, due to the development of morphine tolerance. Co-injections of pentazocine (0.1, 0.3, and 1.0 mg . kg(-1)) with morphine potentiated the morphine-induced antinociception dose-dependently by preventing the development of morphine tolerance. Nor-binaltorphimine completely inhibited the chronic antinociception maintained by co-injections of morphine and pentazocine. Conclusion. When chronically co-administered with morphine, pentazocine at low, subanalgesic doses dose-dependently potentiated morphine-induced antinociception in morphine-tolerant mice, through its kappa-opioid-receptor-mediated tolerance-preventing activity. Because pentazocine is the only agonist-antagonist analgesic that has an effective oral formulation suitable for chronic administration, the results of the present study warrant clinical trials of pentazocine to assess its tolerance-preventing activity in patients with cancer pain.