Long term hyperalgesia mediated by spinal dorsal horn

损伤后疼痛的增强在几分钟内剧烈发生，并可持续数天或数周。在某些情况下，增强疼痛可以无限期地持续下去，要么是因为损伤无法修复，要么是因为一些未知的机制可能与外周损伤无关。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引起中枢神经系统的深刻变化，这些变化很难改变，这是慢性疼痛的原因。慢性疼痛已被证明对受影响的个体非常虚弱，并且对大多数治疗都是难治性的。我们假设疼痛传递被持续的伤害性输入所改变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敏化（见项目2和3）一样，外周伤害感受器的长期脊髓敏化（见项目2和3），脊髓的长期敏化可能需要一系列因素的结合，包括受损的外周组织、该组织的传入交通和脊髓对外周损伤的反应。我们建议理解，长期的脊髓致敏需要系统的操作和评估外周、传入和中枢效应的组合，这些效应被单独地认为是持续疼痛的原因。一旦了解了这些因素，就可以制定合理的治疗方法。未来5年的具体目标是：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. 是否传入活动的阻断、末梢神经的轴突运输破坏a)影响外周注射福尔马林产生的胶质细胞激活和异位性痛觉/痛觉过敏，和/或b)产生胶质细胞激活和异位性痛觉/痛觉过敏而不损害外周组织。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觉过敏的潜在介质。单传入记录，行为和免疫组织化学的组合将用于大鼠和转基因小鼠来实现这些目标。

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.