Sex hormones regulate the contribution of PKC epsilon and PKA signalling in inflammatory pain in the rat

We have evaluated the contribution of differences in second messenger signa lling to sex differences in inflammatory pain and its control by sex hormon es. In normal male but not female rats, epinephrine-induced mechanical hype ralgesia was antagonized by inhibitors of protein kinase C epsilon (PKC eps ilon), protein kinase A (PKA) and nitric oxide synthetase (NOS). Similarly, in PKC epsilon knockout mice, a contribution of PKC epsilon to epinephrine -dependent mechanical hyperalgesia occurred in males only. In contrast, hyp eralgesia induced by prostaglandin E-2, in both females and males, was depe ndent on PKA and NO. In both sexes, inhibitors of mitogen-activated protein kinase/extracellular-signal related kinase kinase (MEK) inhibited epinephr ine hyperalgesia. In gonadectomized females, the second messenger contribut ions to epinephrine hyperalgesia demonstrated the pattern seen in males. Ad ministration of oestrogen to gonadectomized females fully reconstituted the phenotype of the normal female. These data demonstrate gender differences in PKC epsilon, PKA and NO signalling in epinephrine-induced hyperalgesia w hich are oestrogen dependent and appear to be exerted at the level of the b eta -adrenergic receptor or the G-protein to which it is coupled.