Mechanisms of Neuropathic Pain in Demylenated Nerves

描述（由申请人提供）：损伤神经的炎症反应可能是炎性脱髓鞘疾病（如格林-巴雷综合征）中神经性疼痛产生和维持的关键因素。神经性疼痛是格林-巴利综合征急性期患者（超过89%的患者）的共同特征，从格林-巴利综合征急性期恢复（即外周轴突髓鞘再生）并不能缓解疼痛。事实上，在大约一半的测试患者中，影响大、中型髓鞘纤维的残余神经病变在格林-巴雷综合征急性发作后持续很长时间。据报道，除了神经性疼痛外，神经性病变还包括振动和冷感所需阈值的增加。振动和寒冷的积极感觉症状可能由大、中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敏感化。本提案的目的是通过研究炎症相关的促痛觉因子的产生来研究外周致敏的细胞和分子机制，这些因子可能直接致敏感觉神经纤维和细胞体。我们将确定局灶性神经脱髓鞘动物表现出的慢性皮肤痛觉过敏是否与周围神经系统中激活细胞类型的炎症反应程度以及由此产生的外周源性促炎介质tnft、IL-1P和/或MCP-1相关。此外，我们将确定细胞因子/趋化因子生产的细胞来源和/或其各自的受体。细胞源、炎症介质及其受体是未来药物治疗的潜在靶点。从鉴定的细胞中验证促炎介质的药物作用可以通过分析转录因子NFvcB的激活状态来完成，NFvcB是炎症介质调节的核心。这种炎症性脱髓鞘疾病模型与这些技术的结合，为研究细胞因子/趋化因子对啮齿动物皮肤痛觉过敏的潜在影响提供了前所未有的能力。这些行为、细胞和生化观察将直接推进我们对伴随格林-巴雷综合征和慢性炎症性疼痛过程的神经性疼痛的细胞基础的基本见解。

DESCRIPTION (provided by applicant): 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.