Activation of Estrogen Receptor a Enhances Bradykinin Signaling in Peripheral Sensory Neurons of Female Rats

Numerous studies have demonstrated that females have a higher risk of experiencing several pain disorders with either greater frequency or severity than males. Although the mech-anisms that underlie this sex disparity remain unclear, several studies have shown an important role for sex steroids, such as estrogen, in the modulation of nociception. Receptors for estrogen are present in primary afferent neurons in the trigeminal and dorsal root ganglia, and brief exposure to estrogen increases responses to the inflammatory mediator bradykinin (BK). However, the mechanism for estrogen-mediated enhancement of BK signaling is not fully understood. The aim of the present study was to evaluate the relative con-tributions of estrogen receptora (ERa), ERb, andGprotein–coupled estrogen receptor 1 (GPER) to the enhanced signaling of the inflammatory mediator BK by 17b-estradiol (17b-E2) in primary sensory neurons from female rats in culture (ex vivo) and in behavioral assays of nociception in vivo. The effects of 17b-E2 on BK responses were mimicked by ERa-selective agonists and blocked by ERa-selective antagonists and by small interfering RNA knockdown of ERa. The data indicate that ERa is required for 17b-E2–mediated enhancement of BK signaling in peripheral sensory neurons in female rats