ABSTRACT
Many studies have demonstrated that premenopausal women are at increased risk for various pain disorders. Pain-sensing neurons, termed "nociceptors," in the trigeminal ganglia (TG) and dorsal root ganglia (DRG) express receptors for inflammatory mediators and noxious physical stimuli and transmit signals for central processing of pain sensation. Estrogen receptors (ERs) are also expressed on nociceptors in the TG and DRG, and there is ample literature to suggest that activation of ERs can influence pain mechanisms. However, the mechanism for ER modulation of nociceptor activity is incompletely understood. The aim of this study was to characterize the effect of 17ß-estradiol (17ß-E(2)) on signaling of the inflammatory mediator bradykinin (BK) in primary cultures of rat sensory neurons and a behavioral model of thermal allodynia in rats. Here, we show that exposure to 17ß-E(2) rapidly (within 15 min) enhanced responses to BK in vitro and in vivo. The 17ß-E(2)-mediated enhancement of BK signaling was not blocked by the transcription inhibitor anisomycin and was mediated by a membrane-associated ER. The effect of 17ß-E(2) to enhance BK responses required activation of ß1-containing, RGD-binding integrins. These data show that 17ß-E(2) rapidly enhances inflammatory mediator responses both in vitro and in vivo and suggest that 17ß-E(2) acting at primary sensory pain neurons may participate in regulating the sensitivity of women to painful stimuli.