Mechanisms of Neuropathic Pain in Demylenated Nerves

脱髓鞘神经中神经病理性疼痛的机制

• 批准号: 7094854
• 负责人: FLETCHER A WHITE
• 金额: $ 29.15万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094854
• 关键词: behavior; chemokine; cytokine; hyperalgesia; myelinopathy; neurons; pain; receptor; sciatic nerve; syndrome; tissues

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.

描述（由申请人提供）：损伤神经中的炎症反应可能是炎症性脱髓鞘疾病（如格林-巴利综合征）中神经性疼痛产生和维持的关键促成因素。神经性疼痛是患有格林-巴利综合征急性期的个体（超过89%的患者）的常见特征，并且从格林-巴利综合征急性期的恢复（即外周轴突的髓鞘再生）不提供疼痛缓解。事实上，大约一半的受试患者在格林-巴利综合征急性发作后，影响大中型有髓纤维的残留神经病变持续很长时间。除了神经性疼痛之外，报告的神经病还包括振动和冷感觉所需的阈值增加。振动和寒冷的阳性感觉症状可能是由大直径和中等直径纤维的延迟髓鞘再生解释的。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致敏。该建议的目的是通过研究炎症相关的促痛因子的产生来检查外周致敏的细胞和分子机制，这些促痛因子可能直接使感觉神经纤维和细胞体致敏。我们将确定慢性皮肤痛觉过敏的动物表现出局灶性神经脱髓鞘是否与周围神经系统中的活化细胞类型的炎症反应的程度和外周衍生的促炎介质TNF α，IL-1 β，和/或MCP-1的产生相关。此外，我们将确定细胞因子/趋化因子生产和/或其各自的受体的细胞来源。细胞源、炎症介质及其受体是未来药物治疗的潜在靶点。来自鉴定的细胞的促炎介质的药物作用的验证可以通过测定转录因子NFvcB的活化状态来完成，所述转录因子NFvcB是调节炎性介质的核心。这种炎性脱髓鞘疾病模型与这些技术的组合提供了前所未有的能力来研究细胞因子/趋化因子对啮齿动物皮肤痛觉过敏的潜在影响。这些行为、细胞和生物化学观察将直接推进我们对伴随格林-巴利综合征和慢性炎性疼痛过程的神经性疼痛的细胞基础的基本见解。