Epinephrine produces sexually dimorphic beta(2)-adrenergic receptor-mediated
mechanical hyperalgesia, with male rats exhibiting greater
hyperalgesia. Because female rats have higher plasma
epinephrine levels, and
beta-adrenergic receptor sensitivity is affected by chronic exposure to agonists, we tested the hypothesis that this sexual dimorphism is due to
epinephrine-induced desensitization of beta(2)-adrenergic receptors. Following
gonadectomy,
epinephrine hyperalgesia, as measured by the Randall-Selitto paw-withdrawal test, was unchanged in male rats while in females it was increased. Prepubertal male and female rats do not demonstrate sexual dimorphism in either plasma
epinephrine level or
epinephrine-induced
hyperalgesia. Adrenal medullectomy and adrenal
denervation both significantly enhanced
epinephrine hyperalgesia, but only in females. In contrast, the sexually dimorphic
hyperalgesia induced by
prostaglandin E(2), another agent that acts directly to sensitize primary afferent nociceptors, was not enhanced by adrenal medullectomy or
denervation. Chronic administration of
epinephrine in male rats, to produce plasma levels similar to those of gonad-intact females, significantly attenuated
epinephrine-induced
hyperalgesia, making it similar to that in females. These results strongly support the suggestion that
estrogen regulates plasma
epinephrine in female rats and differential sensitivity to beta(2)-adrenergic agonists accounts for the sexual dimorphism in
epinephrine-induced
hyperalgesia. Unexpectedly, regulation of adrenal medullary function by
estrogen was also found to modulate baseline nociceptive threshold such that females had a lower nociceptive threshold.