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

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Abstract
The neuromodulatory interactions of sex steroids with the opioid system may result in sex differences in pain and analgesia. Dynorphin is an endogenous kappa-opioid peptide that is upregulated in an animal model of peripheral inflammation and hyperalgesia and is possibly regulated by circulating levels of sex steroids. The present study compared behavioral responses of male, cycling female, and gonadectomized Sprague–Dawley rats in a model of persistent pain. Cycling female rats were behaviorally tested over a 14-day period, and their estrous cycles were monitored by daily vaginal smears. Thermal hyperalgesia was measured by paw withdrawal latencies taken prior to and 24–72 h after rats received a unilateral hindpaw injection of complete Freund's adjuvant (CFA). Prior to CFA administration, there was no significant 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 with male rats, ovariectomized female rats, and female rats in other estrous stages (P≤0.05). Levels of spinal preprodynorphin (PPD) mRNA induction in the L4–L5 segments were assessed by Northern blot analysis. PPD mRNA expression ipsilateral to the injected paw was significantly higher in female rats in diestrus (P≤0.05) and proestrus (P≤0.01) compared with rats in estrus and intact male rats. Ovariectomized rats had significantly higher levels of PPD mRNA expression compared with intact male rats (P≤0.05). However, castrated male rats had significantly lower levels of PPD mRNA expression than intact male rats (P≤0.05). PPD mRNA expression was not altered on the contralateral side of the spinal cord in any group. These results suggest a hormonal regulatory influence on the response 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.