基于artemin/GFRα3调控TRP通道探讨当归四逆汤镇痛作用机制

The incidence of peripheral neuropathic pain like disease is high and difficult to cure. The temperature sensitive TRP channel is the ignition device that triggers the peripheral sensitization of NP. Danggui Sini decoction has bidirectional regulation effect: it can inhibit the cold channel of TRP to improve the cold pain sensitivity, but also can inhibit the hot channel of TRP to improve its heat and mechanical pain sensitivity. This study proposed a working hypothesis: "the therapeutic effect of Danggui Sini decoction on NP may be based on the regulation of artemin/GFR α 3 to inhibit the TRP channel in DRG and prevent peripheral sensitization."We will use animal behavior, molecular biology, histopathology and other techniques to observe the intervention effect of prophylactic taking Danggui Sini decoction, single medicine, warm medicine combination, cold medicine combination on different properties of pain sensitivity. Changes in the expression of TRP cold and hot channels on DRG neurons。The analgesic molecular mechanism of the upstream target artemin/GFR α 3, which regulates both cold and hot TRP channels, and its regulatory pathway p38 MAPK was studied.To explain the scientific connotation of treating cold pain with warm heat medicine and heat pain with cold cooling medicine and its compatibility, the expected results will not only provide the basis for clinical accurate use of this prescription, but also provide experimental basis for its compatibility.

外周神经病理性疼痛类疾病（NP）发病率高且难以根治，用当归四逆汤疗效良好。温度敏感TRP通道是触发NP外周敏化的点火装置。前期研究发现，当归四逆汤具有双向调节作用：既能抑制TRP冷通道改善冷痛敏，也能抑制TRP热通道改善其热和机械痛敏。本研究提出工作假说：“当归四逆汤对NP的治疗作用，其主要机制可能基于artemin/GFRα3调控从而抑制DRG中的TRP通道，阻止外周敏化。”拟应用动物行为学、分子生物学、组织病理学等技术，观察当归四逆汤全方、单味药、温热药组合、寒凉药组合对不同性质痛敏的干预效果，DRG上冷、热TRP通道表达变化；并重点研究该方对冷、热TRP通道均有调控作用的上游靶点artemin/GFRα3，及其调控途径p38MAPK的镇痛分子机制。诠释温热药、寒凉药分别治疗寒痛、热痛，及其全方配伍的科学内涵；预期成果将不仅为该方临床精准用方提供依据，也为该复方配伍提供实验依据。

1..研究背景：外周神经病理性疼痛类疾病（NP）发病率高且难以根治，用当归四逆汤疗效良好。温度敏感TRP通道是触发NP外周敏化的点火装置。.2..研究内容：本项研究采用动物行为学、分子生物学、组织病理学等技术，观察当归四逆汤全方、单味药、温热药组合、寒凉药组合对不同性质痛敏的干预效果，DRG上冷、热TRP通道表达变化；并重点研究该方对冷、热TRP通道均有调控作用的上游靶点artemin/GFRα3. 及其调控途径p38MAPK的镇痛分子机制。诠释温热药、寒凉药分别治疗寒痛、热痛，及其全方配伍的科学内涵。.4.研究结果：⑴在CCI模型上，当归四逆汤不仅能全面下调冷、热敏感的TRP通道在DRG神经元的表达，全面抑制模型动物的冷痛、热痛、机械痛，改善坐骨神经损伤；而且能降低DRG及血清中炎症因子水平，从而抑制外周敏化，抑制损伤神经处施万细胞凋亡，促进损伤神经修复。⑵当归的活性成分阿魏酸和 Z-藁本内酯对 TRPM8 和 TRPA1具有协同抑制作用；阿魏酸、桂枝活性成分肉桂酸、细辛活性成分去甲乌药碱对 TRPA1 激动模型均有抑制作用。⑶当归四逆汤及其活性成分去甲乌药碱能够缓解因寒所致的末梢血液循环不良，改善神经微循环。⑷上述活性成分主要通过TLR4/NF-kB及TLR4/MAPK信号通路抑制神经炎症，促进神经修复。⑸当归四逆汤中，寒凉药芍药、通草及其活性成分对TRP热通道TRPV1-4有抑制作用；而温热药及其活性成分对TRP冷通道TRPA1、TRPM8有抑制作用，但两者具有协同作用。⑹上游靶点artemin/GFRα3对TRP通道的调控作用不明显，而炎性通道p38MAPK调控作用明显。.5..成果：共发表SCI论文15篇，其中中科院1区论文1篇,中科院2区5篇。