Sex differences in opioid antinociception: modulation by the N-methyl-D-aspartate system

There is ample evidence that males and females differ markedly in their sensitivity to the antinociceptive effects of opioids that are active at mu and kappa receptor. The following studies examined the role of the NMDA receptor system in modulating sexually dimorphic opioid antinociception using acute (hot-plate and warm water tail-withdrawal) and persistent (temporal summation and capsaicin) models of nociception. Experiment 1 focused on the development of a behavioral procedure to induce temporal summation in rats and determined the sensitivity of this behavior temporal summation in rats to various parametric manipulations, sex, modulation by the NMDA receptor system, and sensitivity to reversal by opioids. Males displayed slightly higher levels of temporal summation than females. NMDA antagonists attenuated the level of temporal summation in both sexes. There were no sex differences in mu and kappa opioids effectiveness in this procedure. Experiment 2 evaluated sex differences in the antihyperalgesic actions of selected kappa and mixed-action opioids in a persistent pain model and examined the role of the NMDA system to modulate these effects in a sexually-dimorphic manner in rats. In general, kappa opioids were more potent in males when administered both peripherally and systemically. Sex differences were not observed with the mixed-action opioids. The NMDA antagonist dextromethorphan attenuated kappa opioid induced antihyperalgesia in both sexes. In contrast to the findings in acute pain models, antagonism at the NMDA receptor site did not modulate the effects of kappa opioids in a sexually-dimorphic manner. Experiment 3 examined sex differences in the influence of the NMDA antagonist dextromethorphan on mu opioid antihyperalgesia in the capsaicin persistent pain model and two acute nociceptive assays. Dextromethorphan enhanced the antihyperalgesic effect of morphine in males but not females in the capsaicin assay. Enhancement of antinociception was seen in both sexes in the acute pain models, with greater magnitude in males. These findings demonstrate a sexually dimorphic interaction between the NMDA antagonist dextromethorphan and morphine in a persistent pain model that can be quantitatively distinguished from those observed in acute pain models. In summary these experiments demonstrate the importance of pain model in investigations of sex differences in opioid analgesia and its possible mechanisms