Alternatives to Opioids for Chronic Pain -Part III

神经损伤后的疼痛是慢性的，而且对现有的止痛药一直难以奏效。这些神经性疼痛综合征包括去传入疼痛、糖尿病、癌症和缺血性神经病变、幻肢疼痛、三叉神经痛、带状疱疹后神经痛以及手术或创伤引起的神经损伤。神经性疼痛不仅是慢性的和难以治愈的，它还会使人虚弱，并导致极端的身体、心理和社会痛苦。我们研究的广泛和长期目标是阐明神经病理性疼痛的产生和维持的脊髓神经免疫机制。这一知识将使治疗神经性疼痛的新药的开发成为可能，而不会增加药物滥用的负担。在前一资助时期完成的研究提供了大量数据，支持中枢神经系统(CNC)细胞因子在持续性神经病理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，即周围神经损伤后的慢性疼痛是由中枢神经免疫/神经炎症机制维持的。中心假说是，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类和细胞黏附分子的异常表达，从而导致促炎细胞因子和免疫介质的失衡，表现为持续性神经病理性疼痛。将使用下列特定目标验证这一假说：1)评估脊髓MHC II类细胞和细胞黏附分子在神经损伤和急性炎症动物模型中的表达；2)确定周围神经损伤后激活的T细胞或巨噬细胞是否被招募到中枢神经系统；3)继续评估全局或特异性免疫抑制疗法改变感觉伤害性处理的可能性；4)确定上述免疫抑制疗法对脊髓促炎细胞因子、MHC II类和CAM表达的影响。免疫细胞化学、原位杂交、酶联免疫吸附试验、RNS保护试验、特异性药物和非伤害性行为分析将被用于解决这些特定的目的。这些研究完成后，将提供：a)周围神经损伤和急性足底内炎后脊髓MHC II类和CAM表达的动态信息；b)神经损伤后免疫细胞向中枢神经系统募集的数据；c)支持临床神经病理性疼痛治疗的新药理学方法的初步数据；d)进一步了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状态的关系的基础；e)指导未来评估细胞因子和神经免疫激活在慢性疼痛中的作用的研究数据。

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.