Opioids in non-cancer pain: Sex-specific modulation of morphine analgesia by dextromethorphan in mice

Abstract

A growing literature indicates that N-methyl-D-aspartate (NMDA) antagonists modulate opioid analgesia in experimental animals and human beings. The influence of NMDA antagonists on morphine analgesia is widely controversial and almost all studies have employed only male experimental subjects. In this study, we tested the influence of dextromethorphan, a clinically used, non-competitive NMDA antagonist, on morphine analgesia in male and female mice. The analgesic response was measured using the 49oC hot water tail-withdrawal test. Oral and intraperitoneal administration potentiated low-dose morphine analgesia, whereas high-dose morphine analgesia was blocked by dextromethorphan in CD-1 mice. This bidirectional effect was also observed in C57BL/6 and DBA/2 mice, generalizing the observation across strain. In all three strains studied, dextromethorphan modulated morphine analgesia in male but not female mice, suggestive of sex-specific mechanisms in the mediation of morphine analgesia. Further, the effect of dextromethorphan was studied in ovariectomized female mice and in ovariectomized mice chronically treated with estrogen. The ovariectomized mice exhibited a male-like pattern; that is, they were sensitive to modulation by dextromethorphan. Estrogen (5 ug/mice, od. for 7 days, i.p.) treatment of ovariectomized mice produced a reversion back to the female-like pattern of dextromethorphan insensitivity. These findings indicate that modulation of morphine analgesia by dextromethorphan depends on both morphine dose and subject sex. Whether these two factors could partly explain the contradictory results in human clinical studies remains to be determined. We and others have reported sex-specific modulation of kappa-opioid analgesia by non competitive NMDA antagonists; the present findings suggest that such sex-specific modulation can also affect mu-opioid analgesia.