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

描述（由申请人提供）： 神经性疼痛和炎性疼痛经常发生在创伤性神经损伤、脊髓损伤（SCI）和截肢后，代表了VA和更普遍的美国人群未满足的医疗需求。目前可用的治疗通常无效或仅部分有效，部分原因是脱靶心脏和CNS副作用。由于电压门控Na通道（Nav）的活性，背根神经节（DRG）神经元的不适当的自发放电和高反应性是神经病理性和炎性疼痛的主要贡献者。我们的目的是识别和表征Na通道亚型和驱动DRG神经元过度兴奋的功能相关分子，以便我们可以靶向它们以更有效地缓解疼痛。在包括伤害感受器的DGR神经元中几种Na通道亚型的优先表达，以及在神经损伤后另一种亚型的上调（其在CNS或心脏组织中不以高水平存在），使得这些Na通道亚型作为疼痛的治疗靶点具有潜在的吸引力。与结合伴侣的高度特异性相互作用可以调节这些通道的活性，这表明Na通道伴侣的靶向可以扩展疼痛的治疗策略。我们最近的进展包括鉴定Na通道Nav1.7作为人类疼痛的关键参与者，并证明三种Na通道亚型Nav1.7，Nav1.8和Nav1.3在疼痛的人类神经瘤中积累。我们还证实了神经瘤中存在几种MAP激酶（激活的p38和ERK 1/2）。我们现在计划通过以下具体目标来巩固我们的进展：1.检查特定的钠通道亚型，其辅助分子和其他相关通道蛋白对实验性神经瘤机械敏感性的贡献。2.分析特定的钠通道亚型，其辅助分子和其他相关通道蛋白在人类疼痛神经瘤中的表达。3.研究FHF 2介导的Nav1.7和Nav1.8 Na通道的调节，这些通道驱动慢性疼痛。4.研究MAPK介导的Nav1.7和Nav1.8 Na通道的调节，其驱动慢性疼痛。5.研究挫伤性SCI是否通过调节Na通道表达或调节其功能特性触发DRG神经元致敏，从而产生增强的伤害感受器过度兴奋和疼痛。 公共卫生相关性： 退伍军人事务部面临的主要健康挑战包括脊髓损伤（SCI;约40，000名退伍军人）;多发性硬化症（MS;影响至少23，000名退伍军人）;神经损伤和创伤性截肢。这些医学病症通常与神经性疼痛和炎性疼痛相关。临床上显著的疼痛影响超过50%的SCI患者和50%至80%的MS患者。目前可用的治疗通常无效或仅部分有效。因此，神经性疼痛和炎性疼痛代表了VA未满足的医疗需求。研究表明，在神经损伤后，由于背根神经节（DRG）神经元的不适当放电而引起疼痛。我们的目标是发现影响DRG神经元行为的分子，以便我们可以确定更有效的治疗神经性疼痛和炎性疼痛的方法。

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. PUBLIC HEALTH RELEVANCE: Among the major health challenges for the Department of Veterans Affairs are spinal cord Injury (SCI; approximately 40,000 veterans); multiple sclerosis (MS; affects at least 23,000 veterans); nerve injury and traumatic limb amputation. These medical conditions are commonly associated with neuropathic pain and inflammatory pain. Clinically significant pain affects over 50 % of patients with SCI, and 50% to 80% of patients with MS. Currently available treatments are often not effective or only partially effective. Neuropathic pain and inflammatory pain, therefore, represent an unmet medical need for the VA. Studies have shown that, following nerve injury, pain arises due to inappropriate firing of dorsal root ganglion (DRG) neurons. Our aim is to discover molecules that affect DRG neuron behavior, so that we can identify more effective treatments for neuropathic and inflammatory pain.