Sex differences in hyperalgesia during morphine infusion: Effect of gonadectomy and estrogen treatment

Morphine treatment can paradoxically increase nociception (i.e. hyperalgesia). Since there are putative sex differences in nociception and morphine sensitivity, we compared nociception in male and female mice using the tail-withdrawal test during continuous infusion of two morphine doses (1.6 and 40.0 mg/kg/24 h). Both doses caused hyperalgesia in both sexes, but onset in females always preceded that of males. Although the larger dose initially evoked analgesia, naltrexone (NTX) pellets implanted prior to morphine infusion abolished analgesia but not hyperalgesia. Distinct sex differences also characterized each morphine dose. Specifically, the lower morphine dose caused hyperalgesia that dissipated after 6 days in males but persisted in females for a minimum of 14 days. Despite this difference, N-methyl-d-aspartate (NMDA) receptor antagonists reversed hyperalgesia in both sexes. In contrast, the higher morphine dose evoked hyperalgesia that resolved concurrently in both sexes, but hyperalgesia was reversed by NMDA receptor antagonists in males only. Ovariectomy (OVX), but not OVX followed by estrogen treatment, abolished both sex differences, and resulted in females exhibiting the male-typical pattern. This study thus demonstrates NTX-insensitive morphine hyperalgesia in females as previously reported for males. However, females utilized hyperalgesic mechanisms which were distinct from those employed by males. Data from females subject to OVX/estrogen replacement further indicate that females possess functional male-typical hyperalgesic mechanisms, but are diverted from their use by ovarian sex steroids. Finally, the finding that each morphine infusion dose was characterized by a unique sex difference provides additional evidence for distinct multiple hyperalgesic systems.