前扣带皮层α2A肾上腺素受体调节自发痛的神经环路研究

About 30 percent of the world population in developed countries were suffering from chronic pain. It is conservatively estimated that there are at least one hundred million of chronic pain patients in China. Statistical research reported that, there are 96% of chronic pain patients accompanied with spontaneous pain. It is still lack of rapid and effective treatment because of the complex pathogenic factors and mechanisms. A2A adrenoceptor (Adra2a) is one of the important targets for the treatment of chronic pain. Our previous study found that Adra2a in the anterior cingulate cortex (ACC) is necessary for the treatment of spontaneous pain after local administration of clonidine, but its neural circuits remain to be further elucidated. The purpose of this project is to identify the specific functional nerve cell type. At the same time, the tracer virus targeting Adra2a promoter will be constructed to search for the upstream and downstream brain regions of Adra2a neurons in the ACC regulating spontaneous pain. And to study the spontaneous pain behavioral changes of Adra2a neurons in ACC after they were activated or inhibited by using optogenetics and pharmacology techniques. Furthermore, the function changes of Adra2a will be explored after peripheral nerve injury too. All of these will provide a new target for the development of new analgesic drugs and theoretical basis for the treatment of chronic pain disorders.

在发达国家中有高达30%以上的人口长期受到慢性痛的困扰，保守估计我国有上亿的慢性痛患者，临床数据表明，有高达96%的慢性痛患者伴有自发痛，因致病因素多、机制复杂，慢性痛尤其是自发痛仍缺乏有效的治疗手段。α2A肾上腺素受体(Adra2a)是治疗慢性痛的重要靶点之一。我们的前期研究发现，前扣带皮层(ACC)中的Adra2a参与镇痛药物可乐定对自发痛的镇痛作用，但其具体的神经环路还有待研究。本项目旨在进一步探索外周神经损伤后，ACC区Adra2a调节自发痛的具体神经细胞类型；寻找ACC区Adra2a神经细胞调控自发痛的上游及下游脑区，阐明Adra2a的神经环路基础；利用光遗传学技术和药理学技术等研究ACC区Adra2a细胞被激活或者抑制后，小鼠自发痛的改变情况；了解Adra2a细胞在外周神经损伤后的功能变化，探明Adra2a在调节自发痛中的神经环路基础，为治疗慢性痛提供理论支持。

在全世界发达国家人口中有高达30%以上长期受到慢性痛的困扰，保守估计中国至少有上亿的慢性痛患者，临床数据表明，有高达96%的慢性痛患者伴随有自发痛。因致病因素多、机制复杂，慢性痛仍缺乏快速有效的治疗手段，特别是自发痛难检测、难治疗、更难预防，到目前为止，对其分子机制和传导通路的研究甚少。我们研究发现，前扣带皮层(anterior cingulate cortex, ACC)的Adra2a在可乐定缓解慢性痛尤其是自发痛方面是必需的，但是其具体的分子机制及神经传导通路尚未有人进行研究，因此研究ACC脑区Adra2a神经细胞的环路基础及此环路对慢性痛调节的具体机制等对治疗慢性疼痛特别是自发痛具有十分重要的意义。本课题首先筛选到了Adra2a基因的启动子序列，随后发现Adra2a神经元主要是兴奋性神经元；利用实时条件位置厌恶实验证实激活ACC脑区的Adra2a神经元可以诱导出小鼠的痛觉厌恶行为；ACC脑区的兴奋性神经元可以投射到红核核团的兴奋性神经元；激活红核核团的兴奋性神经元可以诱导出小鼠的痛觉样行为；抑制外周神经损伤小鼠红核核团的兴奋性神经元可以提高小鼠的痛觉阈值；上述结果说明ACC脑区可以直接投射到红核核团调控小鼠的痛觉样行为，本结果为进一步加深了解慢性痛的神经环路提供了支持，为临床开发新的药物提供了新的策略。