Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the muopioid receptor

Rationale: Recent studies indicate that morphine is more potent as an antin ociceptive agent in male than female rodents and monkeys. Objectives: To ev aluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinotiception in rat strains (F344 a nd Lewis) that display differential sensitivity to morphine antinociception . Methods: Antinociceptive testing was conducted using a rat warm-water (50 -56 degrees C) tail-withdrawal procedure. Dose-response and time-course det erminations were performed with various opioids. Results: Across the nocice ptive stimulus intensities tested, the high-efficacy mu opioids morphine, e torphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more p otent in males, and at higher stimulus intensities more patent and effectiv e (greater maximal effect) in males. At low stimulus intensities, the low-e fficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities w ere more potent and effective in males. At a low stimulus intensity, the mu /kappa opioid nalbuphine was more potent and effective in males. At stimulu s intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagoniz ed the effects of morphine in females. Genotype-related differences were no ted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females. Co nclusions: That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increa ses in the nociceptive stimulus intensity suggests that the relative effica cy of mu opioids as antinociceptive agents is greater in male than female r ats.