Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia

The neuromodulatory interactions of sex steroids with the opioid system may result in sex differences in pain and analgesia. Dynorphin is an endogenou s kappa-opioid peptide that is upregulated in an animal model of peripheral inflammation and hyperalgesia and is possibly regulated by circulating lev els of sex steroids. The present study compared behavioral responses of mal e, cycling female, and gonadectomized Sprague-Dawley rats in a model of per sistent pain. Cycling female rats were behaviorally tested over a 14-day pe riod, and their estrous cycles were monitored by daily vaginal smears. Ther mal hyperalgesia was measured by paw withdrawal latencies taken prior to an d 24-72 h after rats received a unilateral hindpaw injection of complete Fr eund's adjuvant (CFA). Prior to CFA administration, there was no significan t difference in paw withdrawal latencies between male rats, cycling female rats, and ovariectomized female rats. Following CFA administration, female rats in proestrus exhibited significantly increased hyperalgesia compared w ith male rats, ovariectomized female rats, and female rats in other estrous stages (P less than or equal to 0.05). Levels of spinal preprodynorphin (P PD) mRNA induction in the L4-L5 segments were assessed by Northern blot ana lysis. PPD mRNA expression ipsilateral to the injected paw was significantl y higher in female rats in diestrus (P less than or equal to 0.05) and proe strus (P less than or equal to 0.01) compared with rats in estrus and intac t male rats. Ovariectomized rats had significantly higher levels of PPD mRN A expression compared with intact male rats (P less than or equal to 0.05). However, castrated male rats had significantly lower levels of PPD mRNA ex pression than intact male rats (P less than or equal to 0.05). PPD mRNA exp ression was not altered on the contralateral side of the spinal cord in any group. These results suggest a hormonal regulatory influence on the respon se of spinal cord dynorphin neurons to chronic inflammation and furthermore , that the association of the endocrine and opioid systems have the ability to influence an animal's sensitivity to pain. Published for the Internatio nal Association for the Study of Pain by Elsevier Science B.V.