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; 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）：受伤神经中的炎症反应可能是炎症性脱髓鞘疾病（例如Guillain-Barre'综合征）的神经性疼痛产生和维持的关键因素。神经性疼痛是患有Guillain-Barre综合征急性期（超过89％的患者）的个体的共同特征，并且从Guillain-Barre综合征的急性期（即外周轴突的再髓鞘化）中恢复了疼痛。实际上，在大约一半经过测试的患者的一半急性发作后很长一段时间，影响大型和中型骨髓纤维的残留神经病会持续很长时间。报告的神经病还包括除神经性疼痛外，还包括振动和冷感觉所需的阈值。振动和冷的正感觉症状可以通过延迟大型和中直径纤维的延迟再生来解释。然而，与周围神经相关的神经性疼痛的不懈性质表明，周围神经固有的因素和/或受体可能导致长期的外周敏化。该建议的目的是检查通过研究炎症相关的促脂质因子的产生，这些细胞和分子机制可能直接使感觉神经纤维和细胞体敏感。我们将确定受到局灶性神经脱髓鞘的动物表现出的慢性皮肤痛觉过敏是否与周围神经系统中活化细胞类型的炎症反应程度相关，并产生外围衍生的促炎性介导体TNFOT TNFOT TNFOT，IL-1P和/或MCP-1。此外，我们将确定细胞因子/趋化因子产生和/或其各自受体的细胞来源。细胞来源，炎症介质及其受体是未来药物疗法的潜在靶标。可以通过分析转录因子NFVCB的激活状态来验证促炎性细胞的促炎性介质的药物效应，这对于调节炎症介质的调节至关重要。这种炎症性脱髓鞘疾病与这些技术的结合提供了研究细胞因子/趋化因子对啮齿动物皮肤痛觉过敏的潜在影响的前所未有的能力。这些行为，细胞和生化观察结果将直接将我们的基本见解转化为伴随Guillain-Barre'S综合征和慢性炎症性疼痛过程的神经性疼痛的细胞基础。