糖尿病神经病理性痛是糖尿病的主要并发症之一，在前驱糖尿病阶段即可发生，由于对其机制了解甚少，因此缺少有效的治疗。研究表明代谢紊乱可能是造成神经病变影响膜结构与兴奋性的主要诱因。本课题组前期实验发现前驱糖尿病背根节神经元Sortilin表达增高，双孔钾通道（TREK1/2）表达减少，干扰TREK1后动物的痛阈明显下降等新异现象。据此我们推测Sortilin与TREK1/2直接绑定后通过其结构顶端脱落的短肽Spadin介导该绑定体内化降解导致钾电流减小，痛信号增强致痛敏；另外Sortilin介导的神经营养因子分泌可间接下调TREK1/2的功能。为论证该假说，本课题以前驱糖尿病大鼠模型的代谢紊乱为切入点，探究DRG与Sortilin-TREK1/2在神经病理性痛发生和发展中的作用机制。本实验结合多种研究手段，为阐明前驱糖尿病神经病理性痛的发生机制提供实验和理论依据，为防治提供提供新靶点。

Diabetic neuropathic pain is a common complication of diabetes which occurs without hyperglycemia in the prediabetes stage. Such a pain syndrome may complicate the diabetic disease and are very difficult to manage. The mechanisms of pain still remain unclear. Recent studies show that the neuropathy may be induced by metabolic dysfunction. Based on our previous studies, we hypothesize that sortilin directly binds to TREK1/2, and the formation of sortilin-TREK1/2 complex leads to the release of spadin, a sortilin-derived peptide. Spadin can specifically act on this complex that causes sortilin-TREK1/2 internalization and degradation. Additionally, sortilin controls release of neurotrophin and associates with Trk receptors to enhance transport. These neurotrophins and Trk receptors will regulate TREK1/2 and increase pain sensation. In this proposal, this study focuses on the changes in primary sensory neurons (DRG) under metabolic dysfunction in prediabetes. The roles of sortilin-TREK1/2 pathway, which is regulated by metabolic substances, in the development of prediabetic neuropathic pain will be examined. We will investigate the roles and molecular mechanisms of sortilin-TREK1/2 through electrophysiological, molecular biological and behavioral methods. This research may further to reveal the complex mechanism of peripheral pain sensitization and provide new target for clinical therapy.