Progesterone rapidly recruits female-typical opioid-induced hyperalgesic mechanisms

Continuous morphine treatment can paradoxically increase nociception (i.e. hyperalgesia) in male and female mice, but sex differences have been reported. Here, we studied progesterone modulation of these differences by assessing nociception on the tail-withdrawal test in male and female mice rendered hyperalgesic during continuous infusion of two different morphine doses (1.6 and 40.0 mg/kg/24 h). Although the lower morphine infusion dose increased nociception in both sexes by infusion Day 4, this hyperalgesia dissipated by Day 6 in males and ovariectomized females, but not gonadally intact females. A single subcutaneous progesterone (0.0016 mg/kg) injection to males and ovariectomized females on Day 6 caused hyperalgesia to recur within 30 min and to persist for a minimum of 120 min. The larger morphine infusion dose also increased nociception in both sexes on Days 4 and 6. However, the NMDA receptor antagonist MK-801 (0.05 mg/kg) reversed hyperalgesia in males and ovariectomized females but not gonadally intact females on infusion Day 6. Subcutaneous progesterone (0.0016 mg/kg) injection inhibited this reversal in male and ovariectomized female mice but had no effect on nociception in saline-infused mice of either sex. These data confirm our previous findings that male and female mice utilize distinct hyperalgesic mechanisms, and show for the first time that a single progesterone bolus dose can recruit female-typical hyperalgesia in ovariectomized females and males.

Research Highlights►Progesterone restores morphine hyperalgesia in males and ovariectomized females. ►Progesterone also disallows MK-801 to reverse hyperalgesia in these mice. ►These data confirm that male and female mice utilize distinct hyperalgesic mechanisms. ►These data show progesterone recruits female hyperalgesic mechanisms.