A number of studies reported striking differences in antinociceptive responses to morphine as a function of sex. Although sex differences in the sensitivity to morphine are widely characterized in rodents, the underlying causes are not identified. Gonadal steroids are believed to contribute to sex differences in response to opioid-induced antinociception. In rats, morphine is metabolized by glucuronidation to morphine-3-glucuronide (M3G). M3G was found to be a functional antagonist of the actions of morphine. Knowledge about the role morphine glucuronides play in sex-specific responses to the antinociceptive effect of morphine may be useful in evaluating therapeutic outcomes of morphine treatment. The purpose of this project was to investigate the effects of sex on the systemic formation of M3G in rats and to correlate glucuronidation variability with differences in antinociceptive responses to morphine. Female rats showed significantly lower morphine-induced antinociception as compared to male rats; 4.6+/-0.5s vs. 11.7+/-2.2s, respectively. Female rats also demonstrated about three-fold higher maximum plasma levels of M3G compared with male rats; 6.2+/-2.2 microg/ml vs. 1.9+/-0.7 microg/ml, respectively. The M3G:morphine AUC ratio was 6.6:1 in female rats and 0.7:1 in male rats. Gonadectomy only partially eliminated sex differences in morphine antinociception and plasma levels of M3G. The results of this study demonstrate that sex and sex differences in the M3G:morphine plasma ratio may play a role in male-female differences observed in morphine antinociception.