17β-Estradiol Activates Estrogen Receptor β-Signalling and Inhibits Transient Receptor Potential Vanilloid Receptor 1 Activation by Capsaicin in Adult Rat Nociceptor Neurons

There is mounting evidence that estrogens act directly on the nervous system to affect the severity of pain. Estrogen receptors (ERs) are expressed by sensory neurons, and in trigeminal ganglia, 17 beta-estradiol can indirectly enhance nociception by stimulating expression and release of prolactin, which increases phosphorylation of the nociceptor transducer transient receptor potential vanilloid receptor 1 (TRPV1). Here, we show that 17 beta-estradiol acts directly on dorsal root ganglion (DRG) sensory neurons to reduce TRPV1 activation by capsaicin. Capsaicin-induced cobalt uptake and the maximum TRPV1 current induced by capsaicin were inhibited when isolated cultured DRGs neurons from adult female rats were exposed to 17 beta-estradiol (10-100 nM) overnight. There was no effect of 17 beta-estradiol on capsaicin potency, TRPV1 activation by protons (pH 6-4), and P2X currents induced by alpha,beta-methylene-ATP. Diarylpropionitrile (ER beta agonist) also inhibited capsaicin-induced TRPV1 currents, whereas propylpyrazole triol (ER alpha agonist) and 17 alpha-estradiol (inactive analog) were inactive, and 17 beta-estradiol conjugated to BSA (membrane-impermeable agonist) caused a small increase. TRPV1 inhibition was antagonized by tamoxifen (1 mu M), but ICI182870 (10 mu M) was a potent agonist and mimicked 17 beta-estradiol. We conclude that TRPV1 in DRG sensory neurons can be inhibited by a nonclassical estrogen- signalling pathway that is downstream of intracellular ER beta. This affects the vanilloid binding site targeted by capsaicin but not the TRPV1 activation site targeted by protons. These actions could curtail the nociceptive transducer functions of TRPV1 and limit chemically induced nociceptor sensitization during inflammation. They are consistent with clinical reports that female pelvic pain can increase after reductions in circulating estrogens. (Endocrinology 149: 5540-5548, 2008)