EFFECTS OF EXCITOTOXIC INJURY ON SPINAL SENSORY PATHWAYS

脊髓损伤（SCI）后的疼痛状况是患者应对SCI的身体和生命威胁后果所面临的许多挑战之一。 这种情况继续挑战卫生专业人员，所有SCI患者的发病率为60- 80%。 这些患者中有近40%报告严重疼痛，他们愿意用任何功能恢复的机会来缓解疼痛。 如果没有针对理解这种情况的机制的研究，就不可能开发出有效的治疗方法。 为此，该建议的重点是针对评估负责自发性和诱发性疼痛行为的发展，在一个模型，研究负责与SCI相关的不同疼痛状态的病理生理学，生物化学和分子级联反应的细胞事件。 在过去的五年中，SCI的兴奋性毒性模型，依赖于脊髓内注射AMPA/代谢型受体激动剂使君子酸（QUIS），已被用于模拟损伤诱发的谷氨酸升高，并产生类似于缺血性和创伤性SCI后的病理后遗症。 具体目标1的实验将评估星形胶质细胞、小胶质细胞和神经元对兴奋性毒性损伤的反应与自发性和诱发性疼痛行为的发作之间的关系。这些实验的主要焦点将指向将这些响应的时间分布沿着脊髓的纵轴与QUIS注射后疼痛行为的发作相关联。 具体目标2将侧重于建立在不同距离的损伤震中的细胞反应和兴奋性毒性病变后感觉神经元的功能状态的变化之间的生理相关性。 在具体目标1-2中，将努力评价抗炎剂IL-10和/或iNOS抑制剂和NMDA拮抗剂胍丁胺对疼痛行为发作与QUIS损伤后细胞反应和生理变化之间关系的影响。 具体目标3将侧重于评估QUIS注射后的生化变化，特别强调引起感觉回路解剖和功能变化的起始事件，这些变化是SCI后持续性疼痛发作的基础。 特别感兴趣的是细胞骨架蛋白在调节膜流动性和谷氨酸结合位点分布中的作用，沿着炎症介质在脊髓感觉神经元中产生塑性变化中的作用。该研究的长期目标是了解SCI中进行性组织损伤的病理生理和生化机制，并为预防和治疗损伤后慢性疼痛的治疗干预措施的发展提供新的方向。

The condition of pain following spinal cord injury (SCI) is one of many challenges facing patients coping with the physical and life threatening consequences of SCI. This condition continues to challenge health professionals with an incidence of 60-80 percent for all SCI patients. Nearly 40 percent of these patients report severe pain to the extent they would trade any chance of functional recovery for relief of pain. Without research directed towards understanding the mechanisms responsible for this condition it is unlikely that effective treatments will be developed. To this end, the focus of this proposal is directed towards evaluating the cellular events responsible for the development of spontaneous and evoked pain behaviors in a model developed to study the pathophysiological, biochemical, and molecular cascades responsible for different pain states associated with SCI. Over the past five years the excitotoxic model of SCI, which relies upon the intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS), has been used to simulate injury evoked elevations of glutamate and produce a pathological sequella similar to that following ischemic and traumatic SCI. The experiments of Specific Aim 1 will evaluate the relationship between the astrocytic, microglial, and neuronal responses to excitotoxic injury and the onset of spontaneous and evoked pain behaviors. The main focus of these experiments will be directed towards correlating the temporal profile of these responses along the longitudinal axis of the cord with the onset of pain behaviors following QUIS injections. Specific Aim 2 will focus on establishing a physiological correlate between cellular responses at different distances from the injury epicenter and changes in the functional state of sensory neurons following excitotoxic lesions. In Specific Aims 1-2 efforts will be made to evaluate the effects of the anti-inflammatory agent IL-10 and/or the iNOS inhibitor and NMDA antagonist agmatine on the relationship between the onset of pain behaviors and the cellular response and physiological changes following QUIS injury. Specific Aim 3 will focus on an evaluation of the biochemical changes following QUIS injections with a special emphasis on the initiating events responsible for the anatomical and functional changes in sensory circuits that underlie the onset of persistent pain following SCI. Of special interest will be the role of cytoskeletal proteins in the regulation of membrane fluidity and distribution of glutamate binding sites along with the role of inflammatory mediators in producing plastic changes in spinal sensory neurons. The long range goal of the proposed research is to understand the pathophysiological and biochemical mechanisms responsible for the progressive tissue damage in SCI, and to provide new directions for the development of therapeutic interventions for the prevention and treatment of chronic pain following injury.