Mechanisms of Neuropathic Pain in Demylenated Nerves

受损神经中的炎症反应可能是导致 格林-巴利综合征等炎症性脱髓鞘障碍患者神经病理性疼痛的维持。 神经性疼痛是格林-巴利综合征急性期患者的共同特征 综合征(89%以上的患者)和格林-巴利综合征急性期的康复(即 外周轴突的再髓鞘形成)并不能缓解疼痛。事实上，残存的神经病影响到很大- 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 大约一半的接受测试的患者。已报道的神经病包括所需阈值的增加 除神经性疼痛外，还可用于震动和冷感。振动的阳性感官症状 而寒冷可能是大直径和中等直径纤维延迟再髓鞘形成的原因。 然而，与周围神经相关的神经病理性疼痛的持续性质表明 外周神经固有的因素和/或受体可能有助于长期的外周 敏化。这项建议的目的是要研究潜在的细胞和分子机制。 通过研究炎症相关的前痛觉因子的产生来实现外周致敏 可直接敏化感觉神经纤维和细胞体。我们将确定慢性皮肤是否 局灶性神经脱髓鞘动物表现出的痛敏反应与 周围神经系统中活化细胞类型的炎症反应及其产物 外周来源的促炎介质TNFot、IL-1P和/或MCP-1。此外，我们还将 确定细胞因子/趋化因子产生的细胞来源和/或它们各自的受体。蜂窝手机 来源、炎症介质及其受体是未来药物治疗的潜在靶点。 从已鉴定的细胞中验证促炎介质的药效可能是 通过分析转录因子NFVCB的激活状态来完成，NFVCB是 炎性介质的调控。这种炎性脱髓鞘模型的结合 这些技术为研究疾病的潜在影响提供了前所未有的能力。 细胞因子/趋化因子(S)对啮齿动物皮肤痛敏的影响。这些行为、细胞和生化 观察将直接推动我们对神经病理性疼痛的细胞基础的基本见解 伴有格林-巴利综合征和慢性炎症性疼痛过程。

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.