As part of an effort to examine gender-related differences in the abuse liability of morphine, the present parametric study was undertaken to systematically establish whether there are gender-related differences in the antinociceptive activity of morphine in rats. Our results showed that male rats were uniformly more sensitive to the antinociceptive properties of morphine than were females in three different assays, i.e., the hot-plate, tail-flick and abdominal-constriction tests. This enhanced sensitivity to morphine was reflected in the peak antinociceptive effect, the magnitude of antinociception (i.e., area under the time-action curve), the duration of the antinociceptive response and the 50% effective dose. These differences appear to reflect markedly enhanced central nervous system sensitivity to morphine in males, compared with females, because we observed no gender-linked differences in serum levels of morphine after its injection, at the time when peak antinociceptive effects were observed. Furthermore, these gender-related differences appear to be reflected in antinociception thought to be mediated by both spinal and supraspinal mechanisms. Finally, our results suggest that the acute effects of steroids play little role in the gender-related differences observed, because short-term castration did not alter the gender-related differences we observed. Rather, it appears more probable that the organizational effects of steroids during critical periods in development, which determine gender-related distinctions, may be significant in the male-female differences we have observed. In view of a great deal of largely anecdotal data for humans that suggest that there may be gender-related differences in the abuse liability of psychoactive substances, the model described in this paper may provide a means to examine this important issue.