Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations.

In earlier studies, it was shown that male rats were considerably more sensitive to the antinociceptive properties of morphine than females in several antinociceptive assays. The purpose of our studies was to examine whether these male-female differences might be due to differences in the blood and brain levels of morphine attained after its s.c. injection rather than to intrinsic differences in the central nervous system sensitivity to the drug. Our results confirmed that males were considerably more sensitive than females to the antinociceptive properties of morphine on the hot-plate test; the ED50 in males was approximately half that found in females. These sex differences were not unique to morphine because males were also more sensitive to the antinociceptive properties of the potent mu agonist, alfentanil. With respect to the pharmacokinetics of morphine, we found that there was a linear relationship in both males and females between the dose of morphine injected and the blood and brain levels achieved 60 min after the injection when the sex-linked differences in morphine-induced antinociception was greatest; no sex differences were found in the peak levels of morphine attained in blood or brain at any dose of morphine. Furthermore, there were no sex-linked differences in the elimination half-life of morphine from blood and, similarly, there were no differences in the disappearance of morphine from brain. On the basis of these data, it appears that the sex-related differences we have observed between males and females in the response to morphine's antinociceptive activity cannot be explained by differences in the pharmacokinetics of morphine. Rather, it appears that sex differences in morphine-induced antinociception are related to inherent differences in the sensitivity of the brain to morphine.