Sodium Channels in Spinal Cord Injury, Nerve Injury and Neuropathic Pain

描述(由申请人提供)： 神经病理性疼痛和炎症性疼痛在创伤性神经损伤、脊髓损伤(SCI)和截肢后经常发生，代表着退伍军人管理局以及更广泛的美国人口的未得到满足的医疗需求。目前可用的治疗方法往往无效或只有部分有效，部分原因是偏离目标的心脏和中枢神经系统副作用。由于电压门控钠通道(NAV)的活动，背根神经节(DRG)神经元不适当的自发放电和高反应性是神经病理性和炎症性疼痛的主要因素。我们的目标是识别和表征驱动DRG神经元超兴奋性的钠通道异构体和功能相关分子，以便我们可以针对它们来更有效地缓解疼痛。包括伤害性感受器在内的几种钠通道亚型在DGR神经元中的优先表达，以及在神经损伤后另一种在中枢或心脏组织中不存在的亚型的上调，使这些钠通道亚型成为潜在的疼痛治疗靶点。与结合伙伴的高度特异性相互作用可能调节这些通道的活性，这表明以钠通道伙伴为靶点可能扩大疼痛的治疗策略。我们最近的进展包括确认Na通道Nav1.7是人类疼痛的关键参与者，并展示了三种Na通道亚型Nav1.7、Nav1.8和Nav1.3在疼痛的人类神经瘤中的积累。我们还证明了神经瘤中存在几种MAP激酶(激活的p38和ERK1/2)。我们现在计划通过以下具体目标在我们的进展的基础上再接再厉：1.检测特定的钠通道异构体、它们的辅助分子和其他相关的通道蛋白对实验性神经瘤机械敏感性的贡献。2.分析人类痛性神经瘤中特异的钠通道亚型及其附属分子和其他相关通道蛋白的表达。3.研究FHF2对驱动慢性疼痛的Nav1.7和Nav1.8钠通道的调节作用。4.研究MAPK对驱动慢性疼痛的Nav1.7和Nav1.8钠通道的调节作用。5.研究挫伤性脊髓损伤是否通过调节钠通道的表达或调节其功能特性而触发DRG神经元的敏化，从而产生更强的伤害性超兴奋性和痛觉。

DESCRIPTION (provided by applicant): Neuropathic pain and inflammatory pain occur frequently after traumatic nerve injury, spinal cord injury (SCI), and limb amputation, and represent unmet medical needs for VA and, more generally, the U.S. population. Currently available treatments are often ineffective or only partially effective, in part because of off-target cardiac and CNS side effects. Inappropriate spontaneous firing and hyper-responsiveness of dorsal root ganglion (DRG) neurons, due to activity of voltage-gated Na channels (Nav), are major contributors to neuropathic and inflammatory pain. Our aim is to identify and characterize Na channel isoforms and functionally-related molecules that drive DRG neuron hyperexcitability, so that we can target them for more effective pain relief. Preferential expression of several Na channel isoforms in DGR neurons including nociceptors, and the up-regulation after nerve injury of another isoform, which is not present at high levels within the CNS or cardiac tissue, makes these Na channel subtypes potentially attractive as therapeutic targets for pain. Highly specific interactions with binding partners may regulate activity of these channels, suggesting that targeting of Na channel partners may expand therapeutic strategies for pain. Our recent progress has included identification of Na channel Nav1.7 as a key player in human pain, and demonstration of accumulation of three Na channel isoforms, Nav1.7, Nav1.8 and Nav1.3 within painful human neuromas. We have also demonstrated the presence of several MAP kinases (activated p38 and ERK1/2) within neuromas. We now plan to build upon our progress, via the following specific aims: 1. Examine the contribution of specific Na channel isoforms, their accessory molecules, and other related channel proteins to mechanosensitivity in experimental neuromas. 2. Analyze the expression of specific Na channel isoforms, their accessory molecules, and other related channel proteins in human painful neuromas. 3. Study FHF2-mediated regulation of Nav1.7 and Nav1.8 Na channels that drive chronic pain. 4. Study MAPK-mediated modulation of Nav1.7 and Nav1.8 Na Channels that drive chronic pain. 5. Investigate whether contusive SCI triggers sensitization of DRG neurons via regulation of Na channel expression or modulation of their functional properties, thereby producing enhanced nociceptor hyperexcitability and pain.