NEUROMOLECULAR BASIS FOR PAIN IN SCI AND BURN INJURY

脊髓损伤和烧伤疼痛的神经分子基础

• 批准号: 8926405
• 负责人: Stephen Waxman
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926405
• 关键词: Acute; Address; Attenuated; Axon; Burn injury; CCL2 gene; CX3CL1 gene; Cells; Data; Dendritic Spines; Development; Dinoprostone; Etanercept; Figs - dietary; Fractalkine; Frequencies; Goals; Human; Immune; In Vitro; Infiltration; Inflammation; Injury; Interleukin-6; Knock-out; MAPK14 gene; MAPK3 gene; MAPK8 gene; Maintenance; Mediating; Microglia; Minocycline; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphology; Nerve; Neuroglia; Neuroma; Neurons; Nociception; Pain; Pain management; Pathway interactions; Patients; Peripheral; Peripheral nerve injury; Phenytoin; Pilot Projects; Population; Posterior Horn Cells; Progress Reports; Protein Isoforms; Rattus; Relative (related person); Resistance; Signal Transduction; Signaling Molecule; Site; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Spinal cord posterior horn; TNF gene; Testing; Therapeutic; Thermal Hyperalgesias; Thick; Time; Traumatic Nerve Injury; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Vertebral column; base; channel blockers; chemokine; chronic pain; cytokine; dorsal horn; effective therapy; ganglion cell; human TNF protein; in vivo; inhibitor/antagonist; injured; macrophage; mechanical allodynia; neuronal excitability; neutrophil; novel; pain behavior; painful neuropathy; prevent; spinal cord injury pain

DESCRIPTION (provided by applicant): PROJECT SUMMARY Chronic pain occurs frequently after burn injury and spinal cord injury (SCI). Currently available treatments are often ineffective or only partially effective. Relatively little is known about the mechanisms responsible for the onset and persistence of pain following burn injury, despite chronic pain being a frequent complaint of burn- injured and SCI patients. Our goal is to identify and characterize cellular and molecular mechanisms that contribute to pain following burn and spinal cord injuries, with the objective of delineating specific targets for more effective pain management. Our recent progress includes development of a burn injury model in rats that produces long-lasting mechanical allodynia associated with hyperexcitability of spinal cord dorsal horn (DH) neurons, and demonstration that pain and DH hyperexcitability occur concomitant with activation of DH microglia, with the spread of pain paralleled by spreading microglial activation in this model. In addition, we have shown that acute early inhibition of microglial activation attenuates burn-induced mechanical allodynia and DH neuronal hyperexcitability. We have also demonstrated that the maintenance of below-level pain following SCI is associated with activation of microglia, and that some microglial functions are regulated by Na channels and can be attenuated with Na channel blockade. Recently, we have also shown that activated polymorphonuclear neutrophils significantly increase excitability of DRG neurons, as manifested by lowered threshold and increased firing frequency. Our preliminary data indicate that macrophages infiltrate DRG following burn injury and SCI, at a time when pain behavior is evident. We have also shown hyperexcitability in DH neurons in vivo in conjunction with activation of DH microglia following burn injury and SCI. We now plan to build upon our progress, via the following specific aims. 1. Elucidate the molecular changes in DRG and DH neurons, and glia, following burn injury, and examine novel pharmacotherapeutic approaches to pain following burn injury. 2. Investigate the effect of Na channel blockade on the activity of microglia following SCI, and determine whether channel blockade can reduce microglial activation and attenuate pain behavior. 3. Examine if infiltration of macrophages into at- and/or below-level DRG is associated with the development and/or persistence of neuropathic pain following SCI. 4. Determine whether Na channel blockade attenuates macrophage infiltration into DRG following SCI and whether neutralizing TNF-a reduce macrophage infiltration into DRG following SCI. 5. Investigate the effects of macrophages and microglia on the excitability of DRG and DH neurons, and determine whether DRG neuron hyperexcitability following activation of these cells can be prevented via neutralization of cytokines which are expressed by immune cells.

描述（由申请人提供）： 项目摘要 烧伤和脊髓损伤 (SCI) 后经常发生慢性疼痛。目前可用的治疗通常无效或仅部分有效。尽管烧伤和 SCI 患者经常主诉慢性疼痛，但对于烧伤后疼痛发生和持续的机制知之甚少。我们的目标是识别和表征导致烧伤和脊髓损伤后疼痛的细胞和分子机制，目的是描绘更有效的疼痛管理的具体目标。我们最近的进展包括开发大鼠烧伤模型，该模型会产生与脊髓背角（DH）神经元过度兴奋相关的持久机械异常性疼痛，并证明疼痛和DH过度兴奋伴随着DH小胶质细胞的激活而发生，随着传播在该模型中，疼痛的减轻与小胶质细胞激活的扩散同时发生。此外，我们还发现，小胶质细胞活化的急性早期抑制可减轻烧伤引起的机械异常性疼痛和 DH 神经元过度兴奋。我们还证明，SCI 后疼痛水平的维持与小胶质细胞的激活有关，并且一些小胶质细胞的功能受 Na 通道调节，并且可以通过 Na 通道阻断来减弱。最近，我们还发现，激活的多形核中性粒细胞显着增加 DRG 神经元的兴奋性，表现为阈值降低和放电频率增加。我们的初步数据表明，烧伤和 SCI 后，当疼痛行为明显时，巨噬细胞会渗入 DRG。我们还显示了体内 DH 神经元的过度兴奋性以及烧伤和 SCI 后 DH 小胶质细胞的激活。我们现在计划通过以下具体目标继续取得进展。 1. 阐明烧伤后 DRG 和 DH 神经元以及神经胶质细胞的分子变化，并研究烧伤后疼痛的新药物治疗方法。 2. 研究Na通道阻断对SCI后小胶质细胞活性的影响，并确定通道阻断是否可以减少小胶质细胞活化并减弱疼痛行为。 3. 检查巨噬细胞浸润到 DRG 水平和/或以下水平是否与 SCI 后神经性疼痛的发展和/或持续存在相关。 4. 确定 Na 通道阻断是否会减弱 SCI 后巨噬细胞向 DRG 的浸润，以及中和 TNF-a 是否会减少 SCI 后巨噬细胞向 DRG 的浸润。 5.研究巨噬细胞和小胶质细胞对DRG和DH神经元兴奋性的影响，并确定是否可以通过中和免疫细胞表达的细胞因子来预防这些细胞激活后DRG神经元的过度兴奋。