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Sex and Gender Differences in Pain and Inflammation

NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/6J mice

¹Interdepartmental Program in Neuroscience and ²Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles (UCLA), Los Angeles, California; ³Department of Psychology, Texas A&M University, College Station, Texas; ⁴Department of Psychology, Center for Neuroendocrine Studies, Neuroscience and Behavior Laboratory, University of Massachusetts, Amherst, Amherst, Massachusetts; and ⁵Department of Psychology, UCLA, Los Angeles, California

Submitted 28 November 2005 ; accepted in final form 27 March 2006

Multiple studies demonstrate that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported.

pain; antinociception; opioid; hyperalgesia; ovariectomy

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