Prolonged ovarian sex steroid treatment of male rats produces antinociception: identification of sex-based divergent analgesic mechanisms

Simulation of the pregnancy blood concentration profile of 17 alpha-estradiol (E-2) and progesterone (P) in nonpregnant ovariectomized rats has been shown to result in a significant elevation of nociceptive response thresholds. The present report demonstrates that spinal opioid antinociceptive responsiveness to these ovarian steroids is not sex-specific. Treatment of orchidectomized sexually mature males with an analogous regimen of E-2 and P also elicits an antinociception, the robustness and temporal profile of which is comparable with that previously observed in females. Neither E-2 nor P, alone, is sufficient to produce antinociception in male rats, as was previously demonstrated in females. Neurobiological substrates and antinociceptive mechanisms underlying ovarian sex steroid antinociception do, however, exhibit sex specificity. In males, the analgesia resulting from ovarian steroid treatment derives from the independent contributions of spinal kappa and mu, not delta, opioid receptor pathways that are additive, not synergistic. Spinal alpha(2)-noradrenergic receptor activity and its attendant analgesic synergy with spinal opioid systems do not contribute to ovarian sex steroid analgesia in males. This is in contrast to the previous demonstrations that ovarian sex steroid-induced antinociception in females results from antinociceptive synergy between activated spinal kappa/delta opioid as well, as alpha(2)-noradrenergic receptor systems. The current data reveal that ovarian steroid-activated multiplicative spinal antinociceptive pathways that had been demonstrated in female rats are not manifest in their male counterparts. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.