Alternatives to Opioids for Chronic Pain: Part IV

神经病理性疼痛是普遍的、持续的和虚弱的。如果没有有效的治疗方法， 神经病理性疼痛综合征的不良副作用，据估计，在 美国包括糖尿病患者、艾滋病病毒携带者、老年人和遭受创伤的年轻人。 在这份修订后的竞争性续签提案中，我们将上一个资助期的数据应用于 研究以下假设：周围神经损伤通过以下途径激活中枢天然免疫 小胶质细胞Toll样受体4和CD14的表达导致星形胶质细胞激活和 趋化因子的表达，进而表现为持续性神经病理性疼痛。小胶质细胞起主要作用 当星形胶质细胞提供胶质细胞到神经元的信号以维持疼痛状态时，星形胶质细胞在启动级联反应中发挥作用。 我们最近工作中的三个重要发现指导了当前的建议：1)强烈的共刺激 神经损伤后腰段脊髓有B7.2分子的表达，但未见B7.1分子表达。 这些数据提示周围神经损伤后CMS自身免疫的保护性作用。2) 支持先天免疫在神经病理性疼痛中的作用的证据，即TLR4的参与。3)数据 趋化因子单核细胞趋化蛋白-1在神经中的关键作用 损伤所致的痛觉异常。中心假说将通过我们的 实验室调查以下具体目的：1)评估辅助分子CD14的作用 神经损伤后小胶质细胞TLR4反应中的MD-2。2)判断TLR4和CD14是否 导致脊髓趋化因子的表达。3)确定胶质源性趋化因子MCP-1 AS的作用 神经损伤后导致行为障碍的白细胞转运的关键调节因子 过敏症。转基因小鼠，反义ODN，中和抗体， 免疫组织化学、RT-PCR、Western Blot分析、FACS和伤害性行为分析将 用来解决这些特定的目标。这些多学科研究的结果可能会达到顶峰。 在新的药典中治疗和预防慢性神经病理性疼痛因此，具有很高的潜力 临床影响。

Neuropathic pain is prevalent, persistent, and debilitating. There is no effective treatment without untoward side effects for the neuropathic pain syndromes that afflict an estimated 5 million patients in the U.S.including patients with diabetes, HIV,the elderly, and young people who experience trauma. In this revised competitive renewal proposal, we apply data from the previous funding period to investigate the following hypothesis: Peripheral nerve injury activates central innate immunity via microglial Toll-like receptor 4(TLR4) and CD14 expression that leads to astrocytic activation and chemokine expression which in turn manifests as persistent neuropathic pain. Microglia play a major role in initiating the cascade while astrocytes provide the glia-to-neuron signal to maintain pain states. Three important recent findings from our work direct this current proposal: 1) Intense co-stimulatory molecule B7.2 expression but not B7.1 was observed in the lumbar spinal cord following nerve injury. These data suggest a role of protective CMS autoimmunity following peripheral nerve injury. 2) Evidence supporting the role of innate immunity in neuropathic pain, i.e. involvement of TLR4. 3) Data to demonstrate a key role of one chemokine, monocyte chemoattractact protein (MCP)-1 in nerve injury-induced allodynia. The central hypothesis will be tested by using established methods in our laboratory to investigate the following Specific Aims: 1) Assess the role of accessory molecules CD14 and MD-2 in the microglial TLR4 responses after nerve injury. 2) Determine whether TLR4 and CD14 result in spinal chemokine expression. 3) Determine the role of the glial-derived chemokine, MCP-1 as a critical regulator of leukocyte trafficking following nerve injury that results in behavioral hypersensitivity. Genetically altered mice, antisense ODN, neutralizing antibodies, immunohistochemistry, RT-PCR, Western Blot analysis, FACs and nociceptive behavioral assays will be used to resolve these specific aims. The results from these multidisciplinary studies may culminate in novel pharmacopeia to treat and prevent chronic neuropathic pain and thus, has the potential for high clinical impact.