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.

受伤后疼痛的加剧在几分钟内剧烈发生，并可持续几天或几周。在某些情况下，增强的疼痛可以无限期地持续，要么是因为受伤的人无法修复，要么是因为某些未知的机制可能与周围损伤无关。在这种情况下，疼痛被定义为“慢性疼痛”。有人提出，长期暴露在痛苦的刺激下会导致中枢神经系统的深刻变化，这些变化非常难以改变，是慢性疼痛的原因。事实证明，慢性疼痛对受影响的人来说是极其虚弱的，而且对大多数治疗方法都是难治的。我们假设，持续的伤害性输入改变痛觉传递的中枢神经系统位置之一是脊髓。正如许多外周事件导致外周伤害性感受器的短期敏化(见项目2和3)一样，脊髓对外周伤害性感受器的长期敏感化(见项目2和3)很可能需要涉及受损的外周组织、来自该组织的传入交通和脊髓对外周损伤的反应的多种因素的组合。我们认为，理解、长期的脊髓敏感化需要系统地操作和评估外周、传入和中枢效应的组合，这些效应被单独作为持续性疼痛的贡献者。一旦了解了这些因素，就可以开发出合理的治疗方法。未来5年的具体目标是确定：1.初级传入放电在我们目前的长期痛觉过敏模型中的作用。2.周围神经末梢损伤是否阻断传入活动、轴突运输a)影响周围注射福尔马林所致的神经胶质细胞活化和痛觉过敏，和/或b)在不损伤周围组织的情况下产生神经胶质细胞活化和痛觉异常/痛觉过敏。3脊髓胶质细胞(星形胶质细胞和小胶质细胞)的激活是否参与短期和长期痛觉过敏。4.在我们的福尔马林模型中，一些激活星形胶质细胞和小胶质细胞并诱导长期痛敏的潜在介质。在大鼠和转基因小鼠上，将使用单一传入记录、行为和免疫组织化学的组合来实现这些目标。