Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor.

Sustained morphine delivery can paradoxically enhance pain sensitivity in humans1,2 and nociceptive behavior in rodents.3,4 This opioid-induced hyperalgesia is obviously a major challenge to the clinical treatment of pain, for which μ-opioid agonists such as morphine are a mainstay. Interestingly, morphine enhances nociception in mice even when opioid receptors are effectively blocked by concurrent treatment with high doses of the broad-spectrum opioid receptor antagonist, naltrexone,5,6 or absent entirely in mice lacking all three opioid receptor genes,7 indicating that morphine hyperalgesia is independent of previous or concurrent opioid receptor activation. We have recently reported a qualitative sex difference in morphine hyperalgesia.6 Specifically, male and female mice manifest hyperalgesia of equal magnitude and duration during 12 days of continuous morphine (40.0 mg · kg−1 · 24 h−1) infusion, but blockade of N-methyl-d-aspartate (NMDA) receptors with LY235959 or MK-801 markedly reversed hyperalgesia in male mice only. This sex-specific response does not seem to be related to any putative sex-dependent potentiation of morphine analgesia by NMDA receptor antagonists8,9 because mice were concurrently treated with naltrexone during morphine infusion. This sex difference was not attributable to antagonist dosing as well because MK-801 did reverse hyperalgesia in males and ovariectomized females but not in ovariectomized females treated with estrogen. These data collectively indicate that female mice possess functional male-typical NMDA receptor-mediated hyperalgesic mechanisms, but they are diverted from their use by ovarian sex steroids. But what neurochemical system mediates morphine hyperalgesia in intact female mice? There are previous reports that NMDA receptor antagonists effectively reduce κ-opioid analgesia10,11 and nonopioid swim stress-induced analgesia12 in male but not in female mice. In the latter study, MK-801 was an effective antagonist in ovariectomized females but not in ovariectomized females treated with estrogen, which parallels exactly our findings with morphine hyperalgesia. By using genetic and pharmacological tools, Mogil et al.11 subsequently demonstrated the critical contribution of melanocortin-1 receptors to the sex-specific mediation of κ-opioid analgesic mechanisms in intact female mice. Accordingly, we assessed the contribution of this receptor to sex differences in morphine hyperalgesia using MSG606, a selective melanocortin-1 receptor antagonist, and by assaying nociception during morphine infusion in melanocortin-1 receptor-deficient C57BL/6J-Mc1re/e (e/e) mice. The sensitivity of these mutants was compared with that of their genetic background, C57BL/6J (B6) mice.