17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons.
17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons.
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DOI：
10.1210/en.2008-0278
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发表时间：
2008-11
期刊：
影响因子：
4.8
通讯作者：
Shenghong Xu;Ying Cheng;J. Keast;P. Osborne
中科院分区：
文献类型：
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作者：
Shenghong Xu;Ying Cheng;J. Keast;P. Osborne
越来越多的证据表明雌激素直接作用于神经系统，影响疼痛的严重程度。雌激素受体 (ER) 由感觉神经元表达，在三叉神经节中，17β-雌二醇可以通过刺激催乳素的表达和释放来间接增强伤害感受，从而增加伤害感受器转导瞬时受体电位香草酸受体 1 (TRPV1) 的磷酸化。在这里，我们证明 17β-雌二醇直接作用于背根神经节 (DRG) 感觉神经元，以减少辣椒素对 TRPV1 的激活。当从成年雌性大鼠中分离培养的 DRGs 神经元暴露于 17β-雌二醇（10-100 nm）过夜时，辣椒素诱导的钴摄取和辣椒素诱导的最大 TRPV1 电流受到抑制。 17β-雌二醇对辣椒素效力、质子 (pH 6-4) 激活的 TRPV1 以及 α,β-亚甲基-ATP 诱导的 P2X 电流没有影响。二芳基丙腈（ERβ 激动剂）也抑制辣椒素诱导的 TRPV1 电流，而丙基吡唑三醇（ERα 激动剂）和 17α-雌二醇（无活性类似物）则无活性，并且与 BSA（膜不可渗透激动剂）缀合的 17β-雌二醇引起小幅增加。 TRPV1 抑制可被他莫昔芬 (1 µm) 拮抗，但 ICI182870 (10 µm) 是一种有效的激动剂，可模拟 17β-雌二醇。我们得出结论，DRG 感觉神经元中的 TRPV1 可以被细胞内 ERbeta 下游的非经典雌激素信号通路抑制。这会影响辣椒素靶向的香草酸结合位点，但不会影响质子靶向的 TRPV1 激活位点。这些作用可以削弱 TRPV1 的伤害感受器功能，并限制炎症期间化学诱导的伤害感受器敏化。它们与临床报告一致，即循环雌激素减少后女性盆腔疼痛会加剧。
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, 17beta-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 17beta-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 17beta-estradiol (10-100 nm) overnight. There was no effect of 17beta-estradiol on capsaicin potency, TRPV1 activation by protons (pH 6-4), and P2X currents induced by alpha,beta-methylene-ATP. Diarylpropionitrile (ERbeta agonist) also inhibited capsaicin-induced TRPV1 currents, whereas propylpyrazole triol (ERalpha agonist) and 17alpha-estradiol (inactive analog) were inactive, and 17beta-estradiol conjugated to BSA (membrane-impermeable agonist) caused a small increase. TRPV1 inhibition was antagonized by tamoxifen (1 microm), but ICI182870 (10 microm) was a potent agonist and mimicked 17beta-estradiol. We conclude that TRPV1 in DRG sensory neurons can be inhibited by a nonclassical estrogen-signalling pathway that is downstream of intracellular ERbeta. 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.