胰岛素样生长因子2在神经病理性疼痛中的作用及机制研究

Neuropathic pain interferes hundreds of millions of people and brings about heavy socioeconomic burdens. The management of chronic neuropathic pain is challenging for the limited efficacy of current medications. Insulin-like growth factor2 (IGF2) is a multifunctional peptide. It still remains unknown whether IGF2 plays roles in neuropathic pain. Previous study revealed that after binding to IGF2 receptor it activates GSK3β and activity-regulated cytoskeletal-associated protein (Arc) expression. Previous findings suggested a correlation between increased endocytosis and increased GSK3 activation and Arc expression. By regulating membrane trafficking of AMPA receptors, Arc and activation of GSK3 are critical for long-term plasticity. Chronic pain may manifest itself through reorganization of areas related to pain. Late and persistent changes in cortical regions are important for maintaining chronic pain. We hypothesize that IGF2 plays critical roles in neuropathic pain by modulating the long-term plasticity in anterior cingulate cortex (ACC). Using sciatic nerve chronic constriction injury (CCI) model and ACC micro-injection, we test the role of IGF2 in neuropathic pain in the form of spontaneous pain behaviors and provoked pain behaviors. The synaptic GSK3 activity, Arc expression and AMPA receptor in the ACC are also investigated. The synaptic long-term plasticity in ACC is validated by Field Excitatory Post Synaptic Potential (fEPSP). The clarification of roles of IGF2 will contribute to the development of new intervention targets for neuropathic pain.

神经病理性疼痛造成巨大社会经济负担。现有药物疗效有限，寻找新的药物干预靶点成为亟待解决的科学问题。慢性疼痛通过对相关神经区域的重塑而呈现。皮层持续性改变负责慢性疼痛的维持。胰岛素样生长因子2(IGF2)是一种多功能肽，但其是否参与神经病理性慢性疼痛尚不清楚。研究表明,IGF2与IGF2受体结合启动调控内吞的糖原合成激酶3(GSK3)和活性调节细胞骨架相关蛋白(Arc),参与突触AMPA受体膜转运和可塑性。我们假设IGF2通过参与调控前扣带回皮层(ACC)的突触可塑性，在神经性疼痛中有重要作用。利用大鼠坐骨神经慢性缩窄模型，核团微注射方法上调/阻断ACC的IGF2，观察对疼痛行为学的影响，明确IGF2的作用；特异性阻断ACC的GSK3β、Arc表达，观察对疼痛行为学和AMPA受体突触表达的影响；fEPSP验证ACC突触可塑性，探索IGF2参与神经性疼痛的作用机制，为寻找新疼痛干预靶点提供基础

神经病理性疼痛造成巨大社会经济负担。现有药物疗效有限，寻找新的药物干预靶点成为亟待解决的科学问题。慢性疼痛通过对相关神经区域的重塑而呈现。皮层持续性改变负责慢性疼痛的维持。胰岛素样生长因子2(IGF2)是一种多功能肽，但其是否参与神经病理性慢性疼痛尚不清楚。研究表明,IGF2 与IGF2 受体结合启动调控内吞的糖原合成激酶3(GSK3)和活性调节细胞骨架相关蛋白(Arc),参与突触AMPA 受体膜转运和可塑性。我们假设IGF2 通过参与调控前扣带回皮层(ACC)的突触可塑性，在神经性疼痛中有重要作用。利用大鼠保留性神经损伤（spared nerve injury , SNI）神经痛模型，该模型神经痛表达稳定（触诱发痛的机械缩爪阈值（PWT）降低可以长时间稳定维持）、而且仅有机械痛敏、而无冷热觉过敏，可重复性强。核团微注射方法上调/阻断前扣带回皮层（anterior cingulate cortex, ACC） 的IGF2，观察对疼痛行为学的影响。ACC注射IGF2减轻SNI疼痛大鼠的机械痛超敏，显著提高神经痛大鼠的机械缩爪阈值。采用IGF2 –blocking antibody阻断IGF2，可以阻断IGF2对SNI大鼠机械缩爪阈值的作用。Anti-IGF2 receptor (IGF2R) 抗体特异性阻断IGF2R可以阻断IGF2缓解SNIS大鼠机械痛阈值的效应，但阻断IGF1receptor不影响IGF2对神经痛大鼠疼痛行为学的效应。提示IGF2通过IGF2R发挥缓解疼痛作用，而非IGF1R。且IGF2对急性热剌激诱发的疼痛行为学没有影响。提示IGF2只对慢性神经痛有缓解效应，对急性疼痛没有作用。IGF2通过与细胞膜的IGF2R结合，可能激活GSK3β和Arc 表达，进而参与和影响突触的长时程可塑形。IGF2 具有诸多优势，可以穿过血脑屏障；并且以IGFs 为干预靶点的药物，已被开发应用于肿瘤防治等领域。因此，明确IGF2参与疼痛调控的作用及进一步阐明其作用机制，将为发现疼痛治疗新靶点提供新视角。未来具有巨大的临床转化前景。