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: 2898176
• 负责人: Joyce A De Leo
• 金额: $ 22.4万
• 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/2898176
• 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，并且始终如一 对可用的镇痛药的难治。 这些神经性疼痛 综合征包括脱落疼痛，糖尿病，癌症和 缺血性神经病，幻影肢体疼痛，三叉神经痛， 手术或由手术或 创伤。 神经性疼痛不仅是慢性且棘手的，而且是 衰弱并导致极端的身体，心理和社会 困扰。 我们研究的广泛，长期目标是 阐明负责发电的机制 维持神经性疼痛。 这些知识将启用 开发新药物以治疗神经性疼痛而没有 药物滥用的额外责任。 调查机制 神经性疼痛，我们的实验室发展和表征 可靠的大鼠神经病模型称为坐骨神经裂解（SCN） 和脊神经冷冻尿液溶解（SPCN）。 模型产生一个 通过暴露和冻结坐骨神经的局灶性神经病变 （SCN）或近端L5脊神经（SPCN）。 模型 事实证明，由于创造而导致神经性疼痛的研究是理想的选择 可预测和健壮的疼痛行为。 使用我们的神经解 模型和慢性收缩损伤模型（Bennett和XIE， 1988年），我们发现了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。 在此提案中，冷冻尿液溶解模型将是 与其他神经性疼痛模型一起使用，以检验我们的假设和 比较一个实验室中不同模型的神经性疼痛模型。 中央假说 - 脊髓细胞因子激活导致 神经性疼痛 - 将使用我的方法测试 实验室和以下具体目的：1）。特征脊柱 促炎细胞因子表达（IL-1，IL-6和TNF-A）和 神经损伤和急性炎性动物的神经胶质激活 型号。 2）确定细胞因子表达改变的起源 神经损伤后的脊髓。 3）评估细胞因子 操纵作为一种减少疼痛反应的技术 特定的细胞因子拮抗剂和内源性〜抗周期因子。 定量免疫细胞化学，原位杂交，特异性 药理学剂和伤害性行为分析将是 用于解决这些特定目标。 完成后，这些研究 将提供： 有关脊柱炎症细胞因子动力学的信息 在明显的神经损伤后表达和神经胶质激活 已知会产生差异性神经性行为 有关特异性脊柱表达增加的起源的数据 细胞因子 初步数据支持新的药理方法 神经性疼痛 进一步理解神经免疫反应的基础 神经损伤以及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，以评估细胞因子的作用和 慢性疼痛中的神经免疫性激活。