Alternatives to Opioids for Chronic Pain -Part III

治疗慢性疼痛的阿片类药物替代品 - 第三部分

• 批准号: 6334453
• 负责人: Joyce A De Leo
• 金额: $ 34.55万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334453
• 关键词: MHC class II antigen; RNase protection assay; analgesics; behavior test; cytokine; disease /disorder model; enzyme linked immunosorbent assay; glia; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; 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 pf our research is to elucidate spinal neuroimmune 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. Research completed in the previous funding period provides substantial data to support the role of central nervous system (CNC) cytokines in persistent neuropathic pain states. We propose to extend our studies to address the unifying hypothesis that chronic pain following peripheral nerve injury is maintained by central neuroimmune/neuroinflammatory mechanisms. The central hypothesis is that peripheral nerve injury causes an inappropriate CNS expression of Major Histocompatibility Complex (MHC) Class II and cellular adhesion molecules which leads to an imbalance of proinflammatory cytokines and immune mediators that manifests as persistent neuropathic pain. This hypothesis will be tested using the following Specific Aims: 1) Assess the role of spinal MHC Class II and cellular adhesion molecule expression in nerve injury and acute inflammatory animal models; 2) Determine whether activated T-cells or macrophages are recruited into the CNS in response to a peripheral nerve injury; 3) Continue to evaluate the potential for global or specific immunosuppressive therapy yo alter sensory nociceptive processing; 4) Determine the effect of the above immunosuppressive therapy on spinal proinflammatory cytokines, MHC Class II and CAM expression. Immunocytochemistry, in situ hybridiazation, ELISA, RNS protection assays, specific pharmacological agents and noncieptive behavioral assays will be used to resolve these specific aims. When completed, these studies will provide: a) Information o the kinetics of spinal MHC class II and CAM expression following peripheral nerve injury and acute intraplantar inflammation, b) Data on the recruitment of immune cells into the CNS in response to nerve injury; c) Preliminary data to support new pharmacological approaches to the treatment of clinical neuropathic pain; d) a foundation for further understanding the neuroimmune response of nerve injury and the relationship to other central nervous systems inflammatory disease states e) 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，并且对可用的镇痛药持续不良。 这些神经性疼痛综合征包括疼痛，糖尿病，癌症和缺血性神经病，幻影肢体疼痛，三叉神经痛，胸胸神经痛以及由手术或创伤引起的神经损伤。 神经性疼痛不仅是慢性且顽固性的，而且令人衰弱，并引起极端的身体，心理和社会困扰。 我们的研究是广泛的长期目标PF，旨在阐明负责神经性疼痛产生和维持的脊柱神经免疫性机制。 这些知识将使开发新药物可以治疗神经性疼痛，而无需增加药物滥用的责任。 在上一个资金期间完成的研究提供了大量数据，以支持中枢神经系统（CNC）细胞因子在持续性神经性疼痛状态中的作用。 我们建议扩展我们的研究，以解决统一的假设，即通过中央神经免疫/神经炎症机制维持周围神经损伤后慢性疼痛。 中心假设是，周围神经损伤会导致主要组织相容性复合物（MHC）II类和细胞粘附分子的不适当的中枢神经系统表达，从而导致促炎细胞因子和免疫介质的失衡表现出表现为持续性神经病性疼痛。 该假设将使用以下特定目的进行检验：1）评估脊髓MHC II类和细胞粘附分子在神经损伤和急性炎症动物模型中的作用； 2）确定是否响应周围神经损伤，将活化的T细胞或巨噬细胞募集到中枢神经系统中； 3）继续评估全球或特定免疫抑制疗法的潜力。 4）确定上述免疫抑制治疗对脊柱促炎细胞因子，MHC II类和CAM表达的影响。 免疫细胞化学，原位杂交，ELISA，RNS保护测定，特定的药理学剂和非屈服行为分析将用于解决这些特定目标。 完成后，这些研究将提供：a）信息o o脊柱MHC II类和CAM表达的动力学后周围神经损伤和急性的急性倾斜炎症，b）有关神经损伤响应的免疫细胞募集到CNS中的数据； c）初步数据支持治疗临床神经性疼痛的新药理方法； d）进一步理解神经损伤的神经免疫反应以及与其他中枢神经系统炎症疾病的关系e）指导未来的研究，以评估细胞因子和神经免疫激活在慢性疼痛中的作用。