Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids

Rationale: Recent studies indicate that a opioids are generally more potent and effective as antinociceptive agents in male than female rodents. Objec tives: To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower ef ficacy mu opioids buprenorphine and dezocine in F344 and Lewis rats. Method s: Using a warm-water tail-withdrawal procedure, the antinociceptive effect s of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administr ation. Results: Under acute conditions, morphine was more potent in males a nd during chronic morphine administration tolerance development was general ly greater in males. As males were more sensitive to the acute effects of m orphine, the functional chronic morphine dose (i.e., chronic morphine dose/ acute morphine ED50) administered to males was larger than in females. Anal yses of the relationship between the functional chronic morphine dose and t olerance indicated that morphine tolerance development was comparable in ma les and females. Under acute conditions, buprenorphine and dezocine were mo re potent and effective in males. During chronic morphine administration, c ross-tolerance was conferred to these opioids as evidenced by rightward. an d in some cases downward. shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more freque ntly observed in females. Conclusions: That comparable levels of morphine t olerance were obtained in males and females when the functional chronic mor phine dose was taken into consideration suggests that the mechanism underly ing tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic mo rphine administration further suggest that these opioids have lower efficac y at the mu opioid receptor in females.