Effects of capsazepine, a transient receptor potential vanilloid type 1 antagonist, on morphine-induced antinociception, tolerance, and dependence in mice

Repeated morphine treatment has been shown to induce transient receptor potential vanilloid type 1 (TRPV1) expression in the spinal cord, dorsal root ganglion (DRG), and sciatic nerve of a rat model. Increased TRPV1 expression may therefore play a role in morphine tolerance. In this study, we evaluated the hypothesis that blockage of TRPV1 may be useful as an adjunctive pain management therapy. We investigated whether blockage of TRPV1 by capsazepine, a TRPV1 antagonist, affected antinociception, development of tolerance, and physical dependence on morphine in mice. Institute of Cancer Research mice were pretreated with capsazepine and post-treated with morphine acutely and repeatedly. Antinociception and its tolerance were assessed using the hot-plate test. Morphine dependence was examined through the manifestation of withdrawal symptoms induced by naloxone in morphine-dependent mice. Acute capsazepine treatment (5 mg kg(-1), i.p.) potentiated the antinociceptive effects of morphine, as measured by the hot-plate test. Repeated co-treatment of capsazepine (2.5 mg kg(-1) i.p.) with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. The development of morphine dependence was also reduced by capsazepine (1.25 or 2.5 mg kg(-1) i.p.). Our results suggest that TRPV1 antagonists can be used adjunctively to morphine treatment because they strengthen morphine antinociception and prevent the development of tolerance, and also physical dependence, on morphine.