雌激素α受体通过脊髓GRPR通路易化痒觉信息传递的机制

Pruritus usually recurs over a long period of time with negative emotions. This brings a lot of trouble to people's work and life. It has been proved that woman’s feelings of itching are stronger than man's, at the same time, the skin lesions are more serious. It suggesting that estrogen may have an enhancement effect. Besides that, in the middle and late pregnancy, due to the obvious increase in estrogen levels in pregnant women, which may cause the incidence of pruritus increased significantly and even cause damage to pregnant women and the unborn fetus. Our preliminary experiments observed that blocking ERα can reverse the increase in chloroquine (CQ)-induced scratching behavior due to rising of estrogen levels. And estrogen receptor alpha (ERα) promotes itch sensation transmission through GRPR neurons in superficial dorsal horn of the spinal cord. Therefore, this project would start from chloroquine induced itch model, focus on the mechanisms of ERα involved in regulating synaptic plasticity in spinal cord GRPR neurons, nuclear receptor mechanism and membrane receptor mechanism, utilizing multiple transgenic animals, electrophysiological, molecular biological, behavioral pharmacological techniques to clarify the molecular mechanisms of ERα facilitating itch transmission through GRPR neurons and to provide experimental basis and new ideas for the treatment of clinical estrogen-related pruritus, especially pruritus during pregnancy.

瘙痒症通常长期反复发作，伴有负性情绪的产生，严重影响人们的工作生活。文献报道，女性对于瘙痒的感受比男性更强烈，且由于搔抓造成的皮肤损伤也更加严重，提示雌激素可能有促痒作用。另外妊娠中后期，伴随雌激素水平明显升高瘙痒症的发病率显著提高，对孕妇及胎儿均有可能造成伤害。我们的预实验观察到：雌鼠的痒觉敏感性明显高于雄鼠；阻断雌激素α型受体（ERα）能够逆转雌激素水平上升导致氯喹（CQ）诱发搔抓行为的增加；ERα在脊髓背角可能通过胃泌素释放肽受体（GRPR）发挥促痒作用。本研究拟利用CQ诱发瘙痒模型，从ERα参与调节脊髓GRPR神经元的突触可塑性机制，核受体机制和膜受体机制入手，综合运用多种转基因动物，结合电生理学、分子生物学、行为药理学等方法，从动物和细胞两个层面深入研究ERα通过GRPR神经元易化痒觉传递的分子机制，以期为临床上雌激素相关的瘙痒症，尤其是妊娠期瘙痒症的治疗提供实验依据和新的思路。

瘙痒被定义为一种由不同种类的皮肤病或者全身性疾病而引发或伴发的令人不愉悦的主观症状，通常伴有强烈的搔抓欲望。瘙痒症通常长期反复发作，伴有负性情绪的产生，严重影响人们的工作生活。大量研究表明，女性对于瘙痒的感受比男性更强烈，且由于搔抓造成的皮肤损伤也更加严重，提示雌激素可能有促痒作用。另外妊娠中后期，伴随雌激素水平明显升高瘙痒症的发病率显著提高，对孕妇及胎儿均有可能造成伤害。因此，本项目以ERα转基因动物的痒模型（皮内注射氯喹所诱发）为基础，从脊髓背角浅层GRPR神经元这个痒觉信息传递关键节点入手，着眼于共表达ERα与GRPR的神经元，综合运用行为药理学、神经形态学、电生理学、分子生物学等方法，深入研究ERα在痒觉信息传递过程中对于关键节点GRPR神经元的易化作用，进一步探索其分子机制。本研究证明了，雌激素的分布差异参与痒感觉的性别差异；雌激素对痒的调节是在脊髓通过ERα神经元调节GRP-GRPR通路完成的；ERα神经元能够直接接受来自DRG中GRP终末的投射，并通突触后效应促痒；给予雌激素后，PKCλ/p62通路分子被激活，通过调节AMPA受体上膜而非通过影响NMDA受体促痒。本研究利用CQ诱发瘙痒模型，深入研究ERα参与调节脊髓GRPR神经元的突触可塑性机制，胞内信号转导通路机制，深入研究ERα通过GRPR神经元易化痒觉传递的分子机制，为临床上雌激素相关的瘙痒症，尤其是妊娠期瘙痒症的治疗提供实验依据和新的思路。