Alternatives to Opioids for Chronic Pain -Part III

神经损伤后的疼痛是慢性的，并且对现有的镇痛药始终难治。这些神经性疼痛综合征包括神经移行性疼痛、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或外伤引起的神经损伤。神经性疼痛不仅是慢性和难治性的，而且会使人衰弱，并导致极端的身体、心理和社会痛苦。我们研究的长远目标是阐明神经性疼痛产生和维持的脊髓神经免疫机制。这些知识将有助于开发新的药物来治疗神经性疼痛，而不会增加药物滥用的责任。在之前的资助期内完成的研究提供了大量数据来支持中枢神经系统（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，以解决周围神经损伤后慢性疼痛是由中枢神经免疫/神经炎症机制维持的统一假设。主要假设是周围神经损伤导致中枢神经系统主要组织相容性复合体（MHC） II类和细胞粘附分子的不适当表达，导致促炎细胞因子和免疫介质的失衡，表现为持续性神经性疼痛。这一假设将通过以下具体目的进行验证：1)评估脊髓MHC II类和细胞粘附分子表达在神经损伤和急性炎症动物模型中的作用；2)确定周围神经损伤时激活的t细胞或巨噬细胞是否被招募进入中枢神经系统；3)继续评估整体或特异性免疫抑制治疗的潜力，以改变感觉伤害性加工；4)确定上述免疫抑制治疗对脊髓促炎细胞因子、MHCⅱ类及CAM表达的影响。免疫细胞化学、原位杂交、ELISA、RNS保护试验、特定药物和非避孕行为试验将用于解决这些特定目标。完成后，这些研究将提供：a)周围神经损伤和急性足底炎症后脊髓MHC II类和CAM表达动力学信息；b)神经损伤后免疫细胞向中枢神经系统募集的数据；c)支持治疗临床神经性疼痛的新药理学方法的初步数据；d)为进一步了解神经损伤的神经免疫反应及其与其他中枢神经系统炎症性疾病状态的关系奠定基础e)指导未来研究评估细胞因子和神经免疫激活在慢性疼痛中的作用的数据。

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.