Long term hyperalgesia mediated by spinal dorsal horn

脊髓背角介导的长期痛觉过敏

• 批准号: 6470111
• 负责人: ALAN R LIGHT
• 金额: $ 18.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6470111
• 关键词: behavior test; behavioral habituation /sensitization; chronic pain; dorsal horn; genetically modified animals; glia; hyperalgesia; immunocytochemistry; laboratory mouse; laboratory rat; nerve injury; nociceptors; pain threshold

The enhancement of pain following injury occurs acutely within a few minutes, and can last for several days or weeks. In some cases, the enhance pain can last indefinitely, either because the injured cannot be repaired, or because of some unknown mechanism that may not be related to peripheral injury. In these cases, the pain is defined as "chronic pain." It has been proposed that long-term exposure to painful stimuli can cause profound changes in the central nervous system that are very difficult to alter and are the cause of chronic pain. Chronic pain has proven to be extremely debilitating for affected individuals, and has been refractory to most treatments. We hypothesize that one of the CNS locations in which pain transmission is altered by persistent nociceptive inputs is the spinal cord. Just as a number of peripheral events contribute to short-term sensitization of peripheral nociceptors (see Projects 2 and 3), it is likely that long-term spinal cord sensitization of peripheral nociceptors (see Projects 2 and 3), it is likely that long-term spinal cord sensitization requires a combination of factors involving damaged peripheral tissue, afferent traffic from that tissue, and spinal responses to the peripheral injury. We propose that understanding, long-term spinal sensitization requires systematic manipulation and evaluation of combinations of peripheral, afferent and central effects that have been implicated individually as contributors to persistent pain. Once these factors are understood, rational treatments can be developed. The specific aims for the next 5 years are to determine: 1. the contribution of primary afferent firing in our present model of long- term hyperalgesia. 2. whether blockade of afferent activity, axonal transport of peripheral nerve ending destruction a) affects the glial activation and allodynia/hyperalgesia produced by peripheral injection of formalin, and/or b) produces glial activation and allodynia/hyperalgesia without peripheral tissue damage. 3 whether activation of spinal cord glial cells (astrocytes and microglial cells) is involved in short- and long-term hyperalgesia. 4. some of the potential mediators that activate astrocytes and microglia and induce long-term hyperalgesia in our formalin model. Combinations of single afferent recording, behavior, and immunohistochemistry will be used on rats and transgenic mice to accomplish these aims.

受伤后疼痛会在几分钟内急剧加剧，并可能持续几天或几周。在某些情况下，增强的疼痛可以无限期地持续下去，要么是因为受伤的部位无法修复，要么是因为一些与外周损伤无关的未知机制。在这些情况下，疼痛被定义为“慢性疼痛”。“有人提出，长期暴露于疼痛刺激会导致中枢神经系统的深刻变化，这些变化很难改变，并且是慢性疼痛的原因。慢性疼痛已被证明是非常衰弱的受影响的个人，并已难治性的大多数治疗。我们假设，持续性伤害性输入改变疼痛传递的中枢神经系统位置之一是脊髓。正如许多外周事件有助于外周伤害感受器的短期致敏（见项目2和3），外周伤害感受器的长期脊髓致敏（见项目2和3），长期脊髓致敏可能需要涉及受损外周组织，来自该组织的传入交通和脊髓对外周损伤的反应的因素的组合。我们建议，理解，长期的脊髓致敏需要系统的操作和评估的组合的外周，传入和中枢的影响，已牵连单独的贡献者持续性疼痛。一旦了解了这些因素，就可以制定合理的治疗方法。今后5年的具体目标是：1.初级传入放电在我们目前的长时程痛觉过敏模型中的作用。2. 是否阻断传入活动、破坏外周神经末梢的轴突运输a）影响由外周注射福尔马林产生的神经胶质活化和异常性疼痛/痛觉过敏，和/或B）产生神经胶质活化和异常性疼痛/痛觉过敏而不损伤外周组织。3脊髓胶质细胞（星形胶质细胞和小胶质细胞）的激活是否参与了短时程和长时程痛觉过敏。4.在福尔马林模型中激活星形胶质细胞和小胶质细胞并诱导长期痛觉过敏的一些潜在介质。将在大鼠和转基因小鼠上使用单一传入记录、行为和免疫组织化学的组合来实现这些目标。