EFFECTS OF EXCITOTOXIC INJURY ON SPINAL SENSORY PATHWAYS

脊髓损伤（SCI）后的疼痛状况是脊髓损伤患者面临的诸多挑战之一。这种情况继续挑战卫生专业人员，在所有脊髓损伤患者中发生率为60- 80%。这些患者中有近40%的人报告说疼痛严重到他们愿意放弃任何功能恢复的机会来缓解疼痛的程度。如果没有针对了解导致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，本提案的重点是在一个模型中评估负责自发和诱发疼痛行为发展的细胞事件，该模型旨在研究与SCI相关的不同疼痛状态相关的病理生理、生化和分子级联反应。在过去的五年中，脊髓损伤的兴奋毒性模型依赖于脊髓内注射AMPA/代谢受体激动剂quisquic酸（QUIS），已被用于模拟损伤引起的谷氨酸升高，并产生类似于缺血性和外伤性脊髓损伤后的病理后遗症。特异性目的1的实验将评估星形细胞、小胶质细胞和神经元对兴奋性毒性损伤的反应与自发和诱发性疼痛行为的发生之间的关系。这些实验的主要焦点将是将这些反应沿脊髓纵轴的时间分布与QUIS注射后疼痛行为的发生联系起来。特异性目标2将侧重于建立与损伤中心不同距离的细胞反应与兴奋性毒性病变后感觉神经元功能状态变化之间的生理关联。在Specific Aims 1-2中，我们将努力评估抗炎剂IL-10和/或iNOS抑制剂和NMDA拮抗剂agmatine在QUIS损伤后疼痛行为的发生与细胞反应和生理变化之间的关系。具体目标3将侧重于评估QUIS注射后的生化变化，特别强调在脊髓损伤后持续疼痛的基础上引起感觉回路解剖和功能变化的启动事件。特别感兴趣的将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，以及炎症介质在脊髓感觉神经元产生可塑性变化中的作用。本研究的长期目标是了解脊髓损伤进行性组织损伤的病理生理生化机制，为制定预防和治疗损伤后慢性疼痛的治疗干预措施提供新的方向。

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.