Pharmacogenetic analysis of sex differences in opioid antinociception in rats.

Sex differences in opioid antinociception have been reported in rodents and monkeys, with opioids being more potent in males than females. In the present study, the influence of rat strain on sex differences in opioid antinociception was examined in a warm water tail-withdrawal procedure. Antinociceptive tests were conducted with the high-efficacy micro-opioid morphine, and the less efficacious opioids buprenorphine, butorphanol and nalbuphine. Baseline nociceptive latencies were consistently higher in males than their female counterparts. Sex differences in opioid antinociception were observed in all strains tested, with the opioids being more potent and/or effective in males. The magnitude of the sex differences was related to the relative efficacy of the opioid, with morphine, buprenorphine, butorphanol and nalbuphine being on average 2.2-, 2.6-, 15.9- and 11.9-fold more potent in males. Sex differences also varied markedly across strains, with large differences consistently obtained in the F344 and F344-Sasco strains, moderate differences in the ACI, DA, Lewis, Sprague Dawley, Wistar and Wistar-Kyoto strains, and small differences in the Long Evans-Blue Spruce, Long Evans, Brown Norway and Holtzman strains. When compared across strains, there was no relationship between sex differences in nociceptive sensitivity and opioid sensitivity. These findings provide strong support for the role of genetic factors in determining sex differences in opioid antinociception, and suggest that the use of low-efficacy opioids, coupled with the use of rat strains that display small and large sex differences in opioid antinociception, may provide a sensitive tool to investigate the mechanisms underlying sex differences in opioid antinociception.