ALTERNATIVES TO OPIOIDS FOR CHRONIC PAIN--PART II

治疗慢性疼痛的阿片类药物替代品——第二部分

• 批准号: 2713172
• 负责人: Joyce A De Leo
• 金额: $ 21.54万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2713172
• 关键词: analgesics; behavior test; cytokine; disease /disorder model; glia; immunocytochemistry; in situ hybridization; inflammation; inhibitor /antagonist; laboratory rat; nerve injury; neuroimmunomodulation; neuropharmacology; nonhuman therapy evaluation; pain; sciatic nerve

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.

神经损伤后的疼痛是慢性的， 对现有的止痛药无效。 这些神经性疼痛 综合征包括传入神经阻滞疼痛、糖尿病、癌症和 缺血性神经病，幻肢痛，三叉神经痛， 带状疱疹后神经痛和手术引起的神经损伤，或 外伤 神经性疼痛不仅是慢性和顽固性的， 使人衰弱，并导致极端的身体、心理和社会问题， 痛苦 我们研究的广泛而长期的目标是 阐明负责生成和 维持神经性疼痛。 这些知识将使 开发新的药物来治疗神经性疼痛， 滥用药物的额外责任。 为了研究 神经性疼痛，我们的实验室开发和表征 可靠的大鼠神经病模型，称为坐骨神经冷冻松解术（SCN） 和脊神经冷冻松解术（SPCN）。 这些模型产生了一个 坐骨神经暴露和冷冻所致局灶性神经损伤 (SCN)或更近端的L5脊神经（SPCN）。 模型 已被证明是理想的神经性疼痛的研究， 可预测的和强大的疼痛行为。 利用我们的神经松解术 模型和慢性压迫性损伤模型（班尼特和Xie， 1988年），我们已经发现证据表明免疫细胞激活和 免疫细胞产物（细胞因子）有助于产生慢性 疼痛状态。 在这个提议中，冷冻神经溶解模型将是 与其他神经性疼痛模型一起使用来测试我们的假设， 在一个实验室中比较不同的神经性疼痛模型。 核心假设--脊髓细胞因子激活导致 神经性疼痛--将使用我的研究中建立的方法进行测试。 实验室和以下具体目标：1）。表征脊柱 促炎细胞因子表达（IL-1、IL-6和TNF-α）和 神经损伤和急性炎症动物中的胶质细胞活化 模型 2)确定细胞因子表达改变的起源， 脊髓神经损伤后。 3)评价细胞因子 手法作为一种技术，以减少疼痛反应， 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 药理学试剂和伤害感受行为测定将被 用于解决这些具体目标。 这些研究完成后， 将提供： 脊髓炎性细胞因子的动力学信息 不同神经损伤后的表达和胶质细胞活化 产生不同的神经病理行为 关于特异性免疫球蛋白的脊髓表达增加的起源的数据 细胞因子 初步数据支持新的药理学方法， 神经性疼痛 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。 指导未来研究的数据，评估细胞因子的作用， 慢性疼痛中的神经免疫激活