EFFECTS OF EXCITOTOXIC INJURY ON SPINAL SENSORY PATHWAYS

脊髓损伤(SCI)后的疼痛状态是患者面临的众多挑战之一，以应对SCI对身体和生命的威胁。这种情况继续对卫生专业人员构成挑战，所有脊髓损伤患者的发病率为60%-80%。其中近40%的患者报告说严重疼痛，以至于他们愿意牺牲任何功能恢复的机会来缓解疼痛。如果不进行旨在了解导致这种情况的机制的研究，就不太可能开发出有效的治疗方法。为此，这项建议的重点是在一个模型中评估导致自发和诱发性疼痛行为发展的细胞事件，该模型是为了研究与脊髓损伤相关的不同疼痛状态的病理生理、生化和分子级联反应。在过去的五年中，脊髓损伤的兴奋性毒性模型依赖于脊髓内注射AMPA/代谢性受体激动剂Quisquicacid(Quis)，它被用来模拟损伤引起的谷氨酸升高，并产生类似于缺血和创伤性脊髓损伤后的病理Sequella。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和诱发性疼痛行为的开始之间的关系。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注射后疼痛行为的开始相关联。具体目标2将侧重于建立离损伤震中不同距离的细胞反应与兴奋性损伤后感觉神经元功能状态变化之间的生理联系。在特定的目标中，1-2将努力评估抗炎药IL-10和/或iNOS抑制剂和NMDA拮抗剂胍丁胺对丘脑损伤后疼痛行为的开始与细胞反应和生理变化之间的关系的影响。具体目标3将侧重于评估注射Quis后的生化变化，特别强调引起SCI后持续性疼痛发生的感觉回路解剖和功能变化的起始事件。特别令人感兴趣的是细胞骨架蛋白在调节膜流动性和谷氨酸结合部位分布中的作用，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。这项研究的长期目标是了解脊髓损伤后进行性组织损伤的病理生理和生化机制，并为防治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.