ALTERNATIVES TO OPIOIDS FOR CHRONIC PAIN--PART II

神经损伤后的疼痛是慢性的，而且始终如一 对现有的镇痛剂不起作用。这些神经性疼痛 症状包括去传入疼痛、糖尿病、癌症和 缺血性神经病，幻肢痛，三叉神经痛， 手术或手术引起的带状疱疹后遗神经痛和神经损伤 精神创伤。神经病理性疼痛不仅是慢性的、难治的，而且 使人虚弱，并导致身体、心理和社会上的极端 苦恼。我们研究的广泛、长期目标是 阐明产生和产生的机制 神经性疼痛的维持性。这一知识将使 治疗神经病理性疼痛的新药开发 滥用药物的附加责任。探讨其作用机制 神经病理性疼痛，我们的实验室开发并表征了 可靠的坐骨神经冷冻神经松解症(SCN)大鼠神经病模型 和脊神经冷冻神经松解术(SPCN)。这些模型产生了一种 暴露和冷冻坐骨神经所致的局灶性神经损害 (SCN)或L5脊神经更近端(SPCN)。模特们 已被证明是研究由于创造而引起的神经病理性疼痛的理想选择 可预测的和强健的疼痛行为。使用我们的神经松解术 模型和慢性压迫性损伤模型(Bennett和Xie， 1988年)，我们发现有证据表明免疫细胞激活和 免疫细胞产物(细胞因子)导致慢性粒细胞白血病的发生 疼痛状态。在这项提案中，冷冻神经松解术模型将是 与其他神经病理性疼痛模型一起使用来验证我们的假设 在一个实验室里比较不同的神经病理性疼痛模型。 中心假说--脊髓细胞因子激活导致 神经病理性疼痛--将使用我的 实验室和以下具体目标：1)。描述脊柱的特征 促炎症细胞因子表达(IL-1、IL-6和肿瘤坏死因子-α)和 神经损伤和急性炎症动物的神经胶质细胞激活 模特们。2)确定细胞因子表达改变的来源 神经损伤后的脊髓。3)评估细胞因子 手法作为一种减少疼痛反应的技术 特异性细胞因子拮抗剂和内源性~抗细胞因子。 定量免疫细胞化学，原位杂交，特异性 药理药物和伤害性行为分析将是 用来解决这些特定的目标。完成后，这些研究将 将提供： 脊髓炎性细胞因子的动力学研究进展 不同神经损伤后的表达和神经胶质细胞激活 已知会产生不同的神经病行为 脊髓特异表达增加的来源的数据 细胞因子 初步数据支持新的药理学方法 神经病理性疼痛 进一步了解神经免疫反应的基础 神经损伤及其与其他中枢神经系统的关系 炎症性疾病状态。 用于指导未来评估细胞因子作用的研究的数据 慢性疼痛的神经免疫激活。

The pain that follows nerve injury is chronic and consistently refractory to available analgesics. These neuropathic pain syndromes include deafferentation pain, diabetic, cancer and ischemic neuropathies, phantom limb pain, trigeminal neuralgia, postherpetic neuralgias and nerve injury caused by surgery or trauma. Neuropathic pain is not only chronic and intractable, it is debilitating and causes extreme physical, psychological and social distress. The broad, long-term objective of our research is to elucidate mechanisms responsible for the generation and maintenance of neuropathic pain. This knowledge will enable development of new medications to treat neuropathic pain without the added liability of drug abuse. To investigate mechanisms of neuropathic pain, our laboratory developed and characterized reliable rat neuropathy models termed sciatic cryoneurolysis (SCN) and spinal nerve cryoneurolysis (SPCN). The models produce a focal nerve lesion by exposure and freezing of the sciatic nerve (SCN) or the more proximal L5 spinal nerve (SPCN). The models have proved ideal for the study of neuropathic pain due to creation of predictable and robust pain behaviors. Using both our neurolysis models and the chronic constriction injury model (Bennett and Xie, 1988), we have found evidence that immune cell activation and immune cell products (cytokines) contribute to generation of chronic pain states. In this proposal, the cryoneurolysis models will be used with other neuropathic pain models to test our hypothesis and compare different models of neuropathic pain in one laboratory. The central hypothesis--spinal cytokine activation leads to neuropathic pain--will be tested using methods established in my laboratory and the following specific aims: 1). Characterize spinal proinflammatory cytokine expression (IL-1, IL-6 and TNF-a) and glial activation in nerve injury and acute inflammatory animals Models. 2) identify the origin of altered cytokine expression in the spinal cord following nerve injury. 3) Evaluate cytokine manipulations as a technique to diminish pain responses using specific cytokine antagonists and endogenous ~anti-cytokines.~ Quantitative immunocytochemistry, in situ hybridization, specific pharmacological agents and nociceptive behavioral assays will be used to resolve these specific aims. When completed, these studies will provide: Information on the kinetics of spinal inflammatory cytokine expression and glial activation following distinct nerve injuries known to produce differential neuropathic behaviors Data on the origin of increased spinal expression of specific cytokines Preliminary data to support new pharmacological approaches to neuropathic pain A foundation for further understanding the neuroimmune response of nerve injury and the relationship to other central nervous system inflammatory disease states. Data to guide future studies that evaluate the role of cytokines and neuroimmune activation in chronic pain.