Characterization of estradiol‐mediated, rapid enhancement of bradykinin signaling in sensory neurons

Abstract

Premenopausal women are at increased risk for numerous pain disorders. Although this sex difference is far from understood, many studies have shown the importance of estrogen in the enhancement of nociceptive signaling. Estrogen receptors (ERs) are present on sensory neurons, and we have previously shown that 17β‐estradiol (E2) rapidly enhances signaling of the inflammatory mediator, bradykinin (BK), in vitro and in vivo. The aim of this study was to further characterize and delineate mechanisms involved in the enhancement of BK signaling by E2. Pretreatment (15 min) with the ERα‐selective agonist, PPT, significantly enhanced BK‐induced PLC activity in cultures of primary sensory neurons and thermal allodynia. The ERβ‐selective agonist, DPN, and the GPR30‐selective agonist, G‐1, had no effect. Enhancement of BK signaling by E2 was seen with pretreatment times ranging from 0 (co‐injection) to 60 min, and persisted for up to 60 min following washout of E2. The effect of E2 was not blocked by the transcription inhibitor anisomycin and was mimicked by E2 conjugated to BSA (membrane impermeable). These data suggest that ERα mediates the rapid onset effect of E2 to enhance BK signaling and that the effect of E2 is non‐genomic.