痛（感）觉传递新“gate”——DRG对外周痛觉信号传递的调控及对疼痛行为的影响

It is assumed that peripheral somatosensory signals are first integrated in the dorsal horn of spinal cord which containing GABA circuit. Spinal cord is considered as the “gate” of pain transmission according to the classical “Gate Control Theory”. We demonstrated in our previous study that there is a similar functional GABA circuit exists in peripheral sensory ganglion, DRG and we proposed that DRG may represent a new type of ‘gate’ within the somatosensory system. This novel notion adds another layer of complexity to the classical “Gate Control Theory” and implies DRG may also represent a novel therapeutic target for pain. In this project, secure direct in vivo evidence for peripheral somatosensory integration at the DRG will be explored to support previous in silicon results though the approach of in vivo electrophysiological recordings from the peripheral and central (dorsal root) aspects of the rat or mouse spinal nerve. Meanwhile, we will test effect of transplantation of GABAergic progenitor cells (medial ganglionic eminence, MGE cells) targeting to GABA circuit within DRG on chronic pain of animals. Taken together, this project will produce strong impact on two levels. i) It will further strengthen and expand the theory we proposed that DRG represents a new type of ‘gate’ of pain transmission. ii) It will improve this theory to translational level and will provide new ideas and experimental evidence for pain treatment targeting to GABA circuit at the periphery.

经典的疼痛传递门控理论认为脊髓背角因存在GABA回路是痛（感）觉信号发生初步整合的部位，故称之痛觉传递的“gate”。我们前期证明外周感觉神经节DRG中存在类似脊髓背角的GABA回路，提出DRG为疼痛传递过程中的“新gate”的理论。这一新理论为传统的门控理论增加了新一层的重要内容，并提示DRG可作为疼痛治疗的外周靶点。本项目将在原有计算机模拟研究的基础上，通过DRG前后神经纤维在体记录方法进一步寻求DRG内GABA系统对痛觉信号传递调控的在体直接证据；并将探求以DRG内GABA回路为靶点的、GABA能神经元前体干细胞MGE细胞DRG移植对动物慢性疼痛行为的影响。本研究具有两方面的重要意义：1）进一步强化和拓展前期提出的DRG作为疼痛传递新“gate”的创新性理论； 2）为推动该理论向临床应用转化、寻求以DRG内GABA回路为靶点疼痛外周治疗新途径提供重要研究方向和实验依据。

前期我们发现外周感觉神经节（DRG）对疼痛传递具有重要的门控滤过作用，本项目在前期研究的基础上进一步通过实时在体神经放电记录的方法得到了神经节对疼痛传递滤过作用的直接证据，并对其机制进行了深入研究。本项目的研究证明了该滤过作用主要发生在轴突分叉的t-juntion部位；DRG本身存在基础的GABA系统活性，对疼痛传递具有基础的滤过作用；外源激活、或通过GABA能前提细胞移植、或通过关遗传学方法激活DRG内的GABA系统均可对疼痛传递产生移植作用；DRG内的GABA系统激活选择性地对疼痛信号具有更高的滤过作用，其机制与痛觉神经元和非痛觉神经元的结构特征相关；这些结果有力地支持DRG部位的GABA系统是慢性疼痛治疗的重要靶点。