周围神经减压改善PDPN氧化应激，重塑DYN+/SOM+神经元平衡、缓解机械性异常疼痛机制的研究

Mechanical allodynia (MA) is a common symptom of diabetic peripheral neuropathy (DPN). The clinical outcome is unsatisfied due to the complexity of pathological mechanism. Our previous study found that peripheral nerve decompression can improve neural microcirculation and neurorestoration by relieving double-crush of the nerve. However, the pathogenesis of pain symptoms of painful diabetic peripheral neuropathy (PDPN) remains unclear. This project aims to exploring the pathological mechanisms of MA in PDPN, and put forward the hypothesis that MA in PDPN is initiated by nerve compression and then accompanied by the related disorder of microcirculation and oxidative stress, causing central hyperactivity such as disinhibition of inhibitory interneuron and activation of thalamic. Our plan: (1) The LDF value, NO, eNOS, ET-1 mRNA in the sciatic nerve of PDPN rats would be assessed to evaluate neural microcirculation; (2) the contents of NF-κB, SOD, MDA, GSH and ROS, CAT activity and total antioxidant activity would be assessed to evaluate the degree of neural oxidative stress; (3) the GABA transmitters and receptors in SOM+ and DYN+ neurons of the spinal dorsal horn and the relavant afferent information of Aβ nerve fibers would be measured. We also plan to acquire fALFF value, Reho value and FC statistic chart through resting fMRI to evaluate thalamic activation. The aim of this study is to elucidate the mechanisms of peripheral nerve decompression in the treatment of MA in PDPN at the molecular and cellular electrophysiological level.

机械性异常疼痛是痛性糖尿病周围神经病变（PDPN）的典型表现，病理机制的复杂性导致临床疗效不确切。我们前期研究发现：周围神经减压术能够通过解除神经双重卡压，改善糖尿病周围神经病变大鼠神经微循环、促进神经修复，但PDPN的发病机制至今尚不明确。本项目着眼于探索PDPN机械性异常疼痛的病理机制，提出假说：PDPN以神经双重卡压为始动因素，微循环障碍和氧化应激为中间环节，疼痛门控环路兴奋性改变和/或丘脑激活为终末效应。拟通过：测定坐骨神经LDF值、NO、eNOS、ET-1mRNA含量，评价神经微循环功能；测定抗氧化酶、分子和活性氧含量，评价氧化应激程度；测定脊髓后角SOM+和DYN+神经元内GABA递质、受体含量及其接受Aβ神经纤维传入信息，评价疼痛门控环路兴奋性；静息态fMRI扫描评价丘脑激活程度，从分子学和细胞电生理学水平阐明周围神经减压术治疗PDPN机械性异常疼痛的作用机制。

机械性异常疼痛是痛性糖尿病周围神经病变(PDPN)的典型症状，也是患者最主要的就医原因。研究高血糖引起的神经损伤可以为PDPN的复杂发病机制提供基础见解。在本项目研究中，我根据神经传导通路各个损伤点的特征，有针对性地探究PDPN发病机制的各个环节。我们发现PDPN以神经双重卡压为始动因素，周围神经微循环障碍和氧化应激为中间环节，疼痛门控环路兴奋性改变与丘脑激活为终末效应。疼痛组大鼠坐骨神经中氧化应激程度加重，抗氧化应激能力下降，不同时机的减压手术可有不同程度的改善，但均无法恢复至疾病前期水平。fMRI扫描评价丘脑激活程度显示：疼痛组大鼠存在多个脑区的活动强度改变及局部血氧水平功能一致性的改变。单细胞测序结果显示疼痛造成SOM+ 神经元谷氨酸相关递质受体的改变。本项目的相关结果推进了对 PDPN 发展过程中周围及中枢潜在分子机制的理解。