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Sex differences and role of gonadal hormones in development of tolerance to morphine analgesia and glutamate level in the nucleus accumbens of rats: A microdialysis study

Introduction: Sex differences are observed in the development of tolerance to antinociceptive effect of opioid drugs such as morphine, but the underlying mechanisms remain unclear. Critical role of glutamate in the development and maintenance of opioid tolerance has been reported by many investigators. There are also evidences about interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. The present study examined the sex differences and role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. Methods: Intact, gonadectoized and sham-operated male and female rats were used. Morphine (7 mg/kg/day, SC) was administered for 8 days. Response to thermal noxious stimuli were measured by tail-flick test. Tolerance was defined as the response which was not significantly different from baseline. Results: The results showed that after chronic morphine administration, antinociceptive tolerance in male rats was significantly greater than females (P<0.05). Sex differences in morphine tolerance disappeared with gonadectomy of animals. There was also significant sex difference in glutamate level in nucleus accumbens of morphine tolerant rats (P<0.05), Glutamate level was decreased after ovariectomy of female rats (P<0.05), but gonadectomy had not significantly effect on glutamate level in males. Conclusion: Results of this study provide evidence of sex differences in development of tolerance to morphine in rats and mediatory roles of gonadal hormones and glutamate levels in these differences.