Male rodents display greater systemic morphine antinociception than females which show their most marked effects during late diestrus or proestrus. Morphine (1-2.5 mug) antinociception on the tail-flick test elicited from the ventrolateral periaqueductal gray was examined across estrus phases in female relative to male rats. Morphine antinociception was greatest in magnitude and potency in males followed by females tested during the proestrus phases relative to estrus and met-diestrus. These data confirm morphine's systemic effects, implicate the ventrolateral periaqueductal gray in estrus phase-mediated effects, and underscore the control of the phase of the estrus cycle in examining sex differences in opioid antinociception.

Male rodents displayed greater magnitudes of analgesia following systemic, ventricular, and intracerebral administration of mu-opioid receptor agonists than female rodents. Whereas neonatal castration of male rat pups produced reductions in systemic and central morphine analgesia as adults, neonatal androgenization of female rat pups treated with testosterone propionate (TP) displayed enhancements in systemic and central morphine analgesia as adults. Adult gonadectomy minimally affected mu-opioid analgesia, except if less potent mu agonists were employed, or if morphine was directly administered into the ventrolateral periaqueductal gray (vlPAG). Adult ovariectomy failed to appreciably alter the enhanced analgesia following systemic morphine in female rats with neonatal androgenization. Because the vlPAG elicited morphine analgesia that was sensitive to both neonatal and adult gonadal hormone manipulations, the present study examined morphine analgesia elicited from the vlPAG in female rats receiving neonatal treatment with TP or vehicle and subsequently exposed to adult ovariectomy or sham surgery as well as intact male rats. Intact male rats displayed significantly greater magnitudes and potencies in vlPAG morphine analgesia than female rats receiving neonatal treatment with either vehicle or TP. In turn, neonatal androgenization significantly enhanced vlPAG morphine analgesia relative to neonatal vehicle treatment in females. Adult ovariectomy significantly enhanced the magnitude of vlPAG morphine analgesia in female rats receiving neonatal treatment with either vehicle or TP. This demonstrates a strong interaction between neonatal and adult gonadal hormone manipulations in the mediation of vlPAG morphine analgesia in female rats.