DRG局部GABA回路对痛觉外周传递的门控调节

The regulatory model of the pain signaling transmission is the basis for understanding the mechanism and the treatment strategy of pain. Two currently prevailing theories for regulation of pain transmission includes the “gate theory” of the spinal cord which imply a gate control of the peripheral pain signal transmission, and the “labeled line theory” which emphasize the importance of the classified sensory neurons. The structural and functional basis for the gate control theory is the GABA circuit system existing in the dorsal horn of the spinal cord. This application proposes a new theory for pain regulation: the peripheral sensory system in DRG also contains a complete functional GABA circuit, with a function similar to that in the spinal cord. This novel notion will be tested using multiple research approaches including RT-PCR, in situ hybridization, electron microscope visualization, HPLC, patch clamp and DRG slice recording, optogenetics and pain behavioral studies, and computer modeling etc. Two key scientific questions will be answered: Is there a functional GABA circuit in DRG? Will this GABA circuit play an important role in pain transmission? The execution of this proposal will help to establish a new theory for pain regulation, and will add novel and significant progress to the pain research. Furthermore, identification DRG as a peripheral modulating site in pain transduction will provide new therapeutic target and new horizon of drug development in pain research.

痛觉信号的传递调控模式是了解疼痛发生机制及研发治疗措施的基础，是疼痛研究领域的一大热点。目前的痛觉信号传递调控理论包括脊髓对痛觉信号整合的“门控（gate control theory）”理论，以及感觉信号独立传导的“线标（labeled line theory）”理论。其中经典的痛觉 “闸门控制学说”的结构及功能基础是位于脊髓背角的GABA（回路）系统。本申请提出一种新的观点：外周感觉神经节DRG局部也存在完整的GABA功能回路，其功能类似脊髓的痛觉门控功能。本项目将通过分子生物学、组织学、电生理学、免疫电镜、光遗传学和动物行为学、以及计算机模拟分析等方法，结合转基因动物运用，对以上假设加以证明。本项目的实施将建立新的痛觉调控理论，具有高度的创新性和科学价值；同时DRG局部痛觉抑制系统的提出为疼痛治疗提供新的靶点，为开发有效的外周性镇痛药物提供新的思路，具有重要的潜在应用价值。

中枢神经系统一直以来被认为是痛觉信号由外周向中枢的传递过程的整合部位，经典的痛觉 “闸门控制学说”认为疼痛信号的初级整合部位是脊髓背角——基于脊髓背角的GABA（回路）系统。本项目的研究中我们证明了大/小鼠外周感觉神经节DRG局部存在完整的GABA功能回路,并且其功能可调节痛觉信号由外周向中枢的传递；我们发现部分DRG神经元可合成和释放GABA；在体DRG局部给予GABA可减轻动物的炎性和神经病理性疼痛；而DRG局部给予GABAA受体阻断剂可诱发或加重疼痛样行为；通过光遗传和化学遗传学方法激活GABA能DRG神经元也可减轻动物的急慢性疼痛行为；通过电生理学和计算机模拟分析等方法证明了DRG神经元胞体的GABAA受体激活可使神经元去极化和兴奋性减低，该效应最终通过电流分流作用等抑制外周痛觉信号经t-junction部位的传递。综上，本项目提出了一种新的观点：外周感觉神经节具有与脊髓背角类似的疼痛信号整合作用，是疼痛传递过程中的新“Gate”，这一观点为传统的痛觉传递理论增加了新的内容，同时DRG局部痛觉抑制系统的提出为疼痛治疗提供新的靶点，为开发有效疼痛治疗途径物提供了新的思路。