Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function

We have previously shown that activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized rats has an anti-mu opioid analgesic action in male rats. Microinjections of the kappa opioid receptor agonist, U69593, attenuated the increase in tail-flick latency produced by activation of mu opioid receptors located within the ventrolateral periaqueductal gray. There are sex differences in the pain modulating potency of opioid analgesics, including kappa opioid agonists. In the present study, we examined whether activation of kappa opioid receptors within the rostral ventral medulla in lightly anesthetized female rats produces an anti-mu opioid analgesic effect similar to that found in males. We found that in the RVM the same dose of kappa opioid receptor agonist that reduces mu receptor-mediated increase in tail-flick latency in male rats produces a moderate increase in tail-flick latency in female rats. Additionally, we discovered that female rats are significantly more sensitive to the mu opioid agonist, DAMGO, injected into the ventrolateral periaqueductal gray. The results indicate that these two brain structures, which mediate the analgesic effects of opioids, are sexually dimorphic with regard to opioid receptor function.