Sexually Dimorphic Regulation of the Spinal Endomorphin 2 Antinociceptive System

Abstract

Epidemiological, clinical, and experimental studies of pain behavior have shown that women experience greater severity and frequency of chronic pain syndromes than men, as well as greater sensitivity to painful stimuli. An understanding of the physiological basis for these behavioral sex differences could help identify pharmacological targets for sex-specific pain medications. Sexually dimorphic mechanisms of pain physiology have been observed in the endogenous opioid system and in the modulation of pain signaling by sex steroids. In the current project, I explored the mechanisms regulating spinal release of endomorphin 2 (EM2), an endogenous agonist of the mu-opioid receptor (MOR). In one study, I determined that activation of spinal MORs augments spinal EM2 release in males but not females. This mechanism was found to be androgen-dependent in males, but independent of both estrogens and androgens in females. This study also demonstrated that the EM2 released by opioid analgesics contributes to the antinociception they produce in an agonist-dependent, sexually dimorphic manner. In a second study, I determined that in females, estrogens suppress spinal EM2 release, and that the magnitude of this suppression is in phase with the estrous cycle. This study also demonstrated that the suppression of EM2 release requires both ovarian and spinally-derived estrogens, suggesting that these two pools of estrogens act synergistically. Collectively, these studies illustrate specific physiological mechanisms that could underlie sex differences in pain behavior, while also providing new insight into the relationship between the endocrine and nervous systems.