Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence

Abstract In an earlier study, we reported the ability of quercetin to reverse the development of morphine tolerance and dependence in mice. In the present study we have attempted to explore the possible involvement of nitric oxide (NO) system in quercetin reversal of morphine tolerance and dependence in mice. Co‐administration of L ‐N G ‐nitro arginine methyl ester (L ‐NAME) or quercetin with morphine during the induction phase (days 1–9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone precipitated withdrawal jumps. L ‐Arginine administration during the induction phase enhanced the development of tolerance to the antinociceptive effect of morphine but had no effect on the naloxone‐precipitated withdrawal jumps. During the expression phase (day 10) acute administration of quercetin or L ‐NAME reversed, whereas L ‐arginine facilitated naloxone‐ precipitated withdrawal jumps in morphine‐tolerant mice, but none of these drugs affected the nociceptive threshold in morphine‐tolerant mice. Further, co‐administration of quercetin or L ‐NAME with L ‐arginine during the induction phase antagonized the latter effects on the development of morphine tolerance. Also, prior administration of quercetin or L ‐NAME reversed the L ‐arginine potentiation of naloxone‐precipitated withdrawal jumps in morphine‐tolerant mice. The results of the present study suggest that quercetin reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity.