LESION INDUCED CHANGES IN SPINAL ARCHITECTURE & PAIN

病变引起的脊柱结构变化

• 批准号: 6045103
• 负责人: RICHARD E COGGESHALL
• 金额: $ 19.23万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-01-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045103
• 关键词: apoptosis; behavior test; denervation; electrostimulus; glutamate receptor; interneurons; laboratory rat; nerve injury; nervous system regeneration; neural degeneration; neuropharmacology; neuroregulation; neurotoxins; pain; sensory signal detection; spinal cord

Intractable pains are a major public health problem following nerve lesions. The underlying mechanisms are imperfectly understood. Recently, however, large sensory fibers not normally concerned with pain are shown to sprout into pain processing regions following nerve lesions. These large fibers use glutamate as a transmitter, which is neurotoxic in excess. This leads to the basic formulation underlying this proposal, namely that this novel input leads to an outpouring of glutamate from large rapidly firing fibers into a pain processing region, that this outpouring is neurotoxic , that the cells selected for destruction are predominantly inhibitory interneurons, leaving a pain processing region devoid of inhibitory control, and that prevention of this destruction will ameliorate the pain related behaviors that follow nerve lesions. These specific hypotheses test these ideas. 1. That nerve lesions lead to some neuron loss in the main spinal processing region. 2. That stimulating large sensory fibers greatly increase this loss. 3. That this loss is activity dependent. 4. That the loss can be lessened or eliminated by glutamate receptor blockers. 5. That the loss is selective for inhibitory interneurons. 6. That the loss of cells caused by nerve stimulation has behavioral consequences. 7. The stimulation induced cell loss is largely apoptotic in nature. If these hypotheses are borne out, the key factor from a clinical point of view is that the nerve fiber activity that follows a nerve lesion would result in death of inhibitory interneurons in the spinal cord. Accordingly, preventing this activity might ameliorate the loss of inhibitory control and thus have therapeutic utility.

顽固性疼痛是神经损伤后的主要公共卫生问题。其潜在机制尚未完全了解。然而，最近，大的感觉纤维通常不关心疼痛显示发芽到疼痛处理区神经损伤后。这些大纤维使用谷氨酸作为递质，过量的谷氨酸具有神经毒性。这导致了这一提议的基本公式，即这种新的输入导致谷氨酸从大的快速放电纤维中倾泻到疼痛处理区域，这种倾泻是神经毒性的，被选择用于破坏的细胞主要是抑制性中间神经元，留下缺乏抑制控制的疼痛处理区域，并且预防这种破坏将改善神经损伤后的疼痛相关行为。这些具体的假设检验了这些想法。1.神经损伤会导致脊髓主要处理区域的一些神经元丢失。2.刺激大的感觉纤维会大大增加这种损失。3.这种损失取决于活动。4.谷氨酸受体阻滞剂可以减轻或消除这种损失。5.这种损失对抑制性中间神经元是有选择性的。6.神经刺激引起的细胞损失会导致行为后果。7.刺激诱导的细胞损失本质上主要是凋亡。如果这些假设得到证实，从临床角度来看，关键因素是神经损伤后的神经纤维活动将导致脊髓中抑制性中间神经元的死亡。因此，阻止这种活性可能会改善抑制控制的丧失，从而具有治疗效用。