基于CaMKII/caveolin-1通路糖尿病神经痛敏化DRG神经元P2X3受体的上膜转运机制与低频电针的干预作用

Diabetic neuropathic pain (DNP) is one of the most common complications of diabetes. It is characterized by spontaneous burning pain and pain sensitization, and severely affects the patients' life quality. Dorsal root ganglion (DRG) P2X3 receptor plays an important role in DNP sensitization. We found that DRG P2X3 receptor membrane protein level was strengthened in DNP sensitization, and electroacupuncture (EA) with low frequency could effectively suppress the strength, but the mechanism is unclear. Initial studies show that ATP, CaMKII and caveolin-1take part in cell surface trafficking of P2X3 receptor. The project is to adopt a rat model with DNP sensitization. Behavior of pain sensitization, DRG neuron electrical activity, extracellular ATP level, activation of CaMKII/caveolin-1 pathway, and cell surface trafficking of P2X3 receptor in DRG neuron cell body and epidermal terminals, as well as the effects of EA with low frequency on these processes were studied, to clear the regulatory mechanism of CaMKII/caveolin-1 pathway in the processes of extracellular activation, intracellular phosphorylation and cell surface trafficking of DRG P2X3 receptor, and the regulatory mechanism of EA with low frequency in these processes. These will provide a scientific foundation for the drug development for DNP based on the regulation of cell surface trafficking of nociceptive receptors and the elucidation of the mechanism underlying EA treatment of DNP.

糖尿病神经痛是糖尿病最常见的并发症之一，主要表现为自发性烧灼样疼痛、痛觉过敏，严重影响患者生存质量。背根神经节（dorsal root ganglion, DRG）P2X3受体在糖尿病神经痛敏化中起着重要作用。我们前期研究发现在糖尿病神经痛敏化中DRG P2X3受体膜蛋白水平升高，而低频电针能抑制其升高。初步研究表明ATP、CaMKII、caveolin-1参与P2X3受体上膜转运。本项目拟采用大鼠糖尿病神经痛敏化模型，观察痛敏化行为学、DRG神经元电活动、胞外ATP水平、CaMKII/caveolin-1通路激活与P2X3受体上膜转运情况，和低频电针的干预作用，明确基于CaMKII/caveolin-1通路DRG神经元P2X3受体从胞外启动、胞内磷酸化到上膜转运的调控机制和低频电针的干预机制，将为糖尿病神经痛基于痛觉受体上膜转运调控的药物研发和电针治疗糖尿病神经痛的机理阐释提供科学基础。

糖尿病神经痛是糖尿病最常见的并发症之一，主要表现为自发性烧灼样疼痛、痛觉过敏，严重影响患者生存质量。背根神经节（dorsal root ganglion, DRG）P2X3受体在糖尿病神经痛敏化中起着重要作用。我们前期研究发现在糖尿病神经痛敏化中DRG P2X3受体膜蛋白水平升高，而低频电针能抑制其升高。初步研究表明ATP、CaMKII、caveolin-1参与P2X3受体上膜转运。本项目拟采用大鼠糖尿病神经痛敏化模型，观察痛敏化行为学、DRG神经元CaMKII/caveolin-1通路激活与P2X3受体上膜转运情况，和低频电针的干预作用。研究结果表明：一次性大剂量腹腔注射可以建立糖尿病神经痛，糖尿病神经痛大鼠DRG神经元P2X3受体表达增加，CaMKII/caveolin-1通路激活，电针可缓解糖尿病神经痛，其镇痛作用可能与其下调DRG神经元P2X3受体表达，抑制CaMKII/caveolin-1通路有关。. 通过本研究明确了基于CaMKII/caveolin-1通路DRG神经元P2X3受体从胞外启动、胞内磷酸化到上膜转运的调控机制和低频电针的干预机制，将为糖尿病神经痛基于痛觉受体上膜转运调控的药物研发和电针治疗糖尿病神经痛的机理阐释提供科学基础。