Mechanisms of Neuropathic Pain in Demylenated Nerves

损伤神经中的炎症反应可能是产生和 在炎性脱髓鞘疾病如格林-巴利综合征中维持神经性疼痛。 神经性疼痛是格林-巴利综合征急性期患者的常见特征 综合征（超过89%的患者）和从格林-巴利综合征急性期（即 外周轴突的髓鞘再生）不能缓解疼痛。实际上，残余神经病变影响大- 和中等大小的有髓纤维在格林-巴利综合征急性发作后持续很长时间， 大约一半的受试者。报告的神经病变包括所需阈值的增加 除了神经性疼痛之外，还用于振动和冷感觉。振动的积极感觉症状 和寒冷可以通过大直径和中等直径纤维的延迟髓鞘再生来解释。 然而，与周围神经相关的神经性疼痛的持续性质表明， 周围神经固有的因子和/或受体可能有助于长期的周围神经损伤。 致敏这项建议的目的是研究细胞和分子机制的基础上， 通过研究炎症相关的前痛觉因子的产生， 可直接致敏感觉神经纤维和细胞体。我们将确定是否慢性皮肤 局部神经脱髓鞘的动物所表现出的痛觉过敏与 周围神经系统中激活的细胞类型引起的炎症反应以及由此产生的 外周来源的促炎介质TNF α、IL-1 β和/或MCP-1。此外，我们将 鉴定细胞因子/趋化因子产生的细胞来源和/或它们各自的受体。蜂窝 炎症介质及其受体是未来药物治疗的潜在靶点。 来自鉴定细胞的促炎介质的药物作用的验证可能是 通过测定转录因子NFvcB的激活状态来完成，NFvcB是转录因子的核心。 调节炎症介质。这种炎性脱髓鞘模型 这些技术提供了一种前所未有的能力来研究疾病的潜在影响 在啮齿动物中，细胞因子/趋化因子对皮肤痛觉过敏的影响。这些行为的、细胞的和生化的 观察将直接推进我们对神经性疼痛的细胞基础的基本见解， 伴随格林-巴利综合征和慢性炎性疼痛过程。

Inflammatory responses in injured nerves are likely to be key contributing factors in the generation and maintenance of neuropathic pain in inflammatory demyelinating disorders such as Guillain-Barre' Syndrome. Neuropathic pain is a common feature in individuals suffering from the acute phase of Guillain-Barre Syndrome (upwards of 89% of patients) and recovery from the acute phase of Guillain-Barre Syndrome (i.e. remyelination of peripheral axons) does not provide pain relief. In fact, residual neuropathy affecting large- and medium-sized myelinated fibers endures long after the acute attack of Guillain-Barre' syndrome in approximately half of all tested patients. Reported neuropathies include increases in the threshold required for vibration and cold sensation, in addition to neuropathic pain. The positive sensory symptoms of vibration and cold can potentially be explained by delayed remyelination of large and medium diameter fibers. However, the unremitting nature of the neuropathic pain associated with peripheral nerves suggests that factors and/or receptors inherent to the peripheral nerve may be contributing to long-term peripheral sensitization. The aim of this proposal is to examine the cellular and molecular mechanisms underlying the peripheral sensitization by investigating the production of inflammation-associated pro-algesic factors which may directly sensitize sensory nerve fibers and cell bodies. We will determine whether the chronic cutaneous hyperalgesia exhibited by animals subjected to focal nerve demyelination is correlated with the degree of inflammatory response by activated cell types in the peripheral nervous system and the resultant production of the peripherally-derived pro-inflammatory mediators TNFot, IL-1P, and/or MCP-1. In addition, we will identify the cellular sources of cytokine/chemokine production and/or their respective receptors. The cellular sources, inflammatory mediators and their receptors are potential targets for future drug therapies. Verification of the pharmaceutical effects of pro-inflammatory mediators from identified cells may be accomplished by assaying the activation state of the transcription factor, NFvcB, which is central to the regulation of the inflammatory mediators. The combination of this model of an inflammatory demyelinating disease with these techniques offer an unprecedented ability to study the potential influences of cytokine/chemokine(s) on cutaneous hyperalgesia in the rodent. These behavioral, cellular, and biochemical observations will directly advance our fundamental insights into cellular basis of neuropathic pain that accompanies both Guillain-Barre' Syndrome and chronic inflammatory pain processes.