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: 7387385
• 负责人: FLETCHER A WHITE
• 金额: $ 25.95万
• 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/7387385
• 关键词: Acute; Adult; Affect; Afferent Neurons; Analgesics; Animals; Antioxidants; Axon; Behavior; Behavioral; Bilateral; Binding; Binding Sites; Biochemical; Biological Assay; Caliber; Cells; Chronic; Chronic inflammatory pain; Clinical; Complex; Cutaneous; Cytokine Receptors; Demyelinating Diseases; Demyelinations; Development; Dose; Enzyme-Linked Immunosorbent Assay; Esthesia; Event; Exhibits; Fiber; Future; Generations; Genes; Goals; Guillain-Barré Syndrome; Hyperalgesia; I Kappa B-Alpha; In Situ Hybridization; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Lead; Lesion; Link; Lysophosphatidylcholines; Maintenance; Mechanical Stimulation; Mediator of activation protein; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Nature; Nerve; Nerve Fibers; Nerve Growth Factors; Nerve Tissue; Neuroglia; Neurons; Neuropathy; Neurotrophin 3; Nociception; Nuclear; Nuclear Translocation; Outcome; Pain; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Pharmacologic Substance; Pharmacotherapy; Phase; Postoperative Period; Process; Production; Promoter Regions; Rattus; Recovery; Regulation; Reporting; Research Personnel; Residual state; Rodent; Role; Schwann Cells; Sensory; Site; Source; Specific qualifier value; Spinal Ganglia; Symptoms; T-Lymphocyte; Tactile Hyperalgesias; Techniques; Testing; Time; Tissues; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Up-Regulation; afferent nerve; base; beta-Chemokines; cell type; chemokine; chemokine receptor; chronic pain; cytokine; day; fiber cell; human NOS2A protein; immunocytochemistry; inhibitor/antagonist; injured; insight; macrophage; nerve injury; neuronal cell body; neuropathology; neurotrophic factor; painful neuropathy; programs; protein degradation; pyrrolidine dithiocarbamate; receptor; relating to nervous system; release factor; research study; response; sciatic nerve; size; transcription factor; vibration

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.

受损神经的炎症反应可能是产生和产生炎症的关键因素。 维持炎症性脱髓鞘疾病（例如格林-巴利综合征）中的神经性疼痛。 神经性疼痛是格林-巴利急性期患者的一个常见特征 综合症（89% 以上的患者）和格林巴利综合症急性期的恢复（即恢复） 外周轴突的髓鞘再生）不能缓解疼痛。事实上，残余神经病变影响大 中等大小的有髓纤维在格林-巴利综合征急性发作后仍能持续很长时间 大约一半的测试患者。报告的神经病包括所需阈值的增加 除了神经性疼痛之外，还可以治疗振动和冷感。振动的积极感觉症状 寒冷可能是由于大直径和中直径纤维的髓鞘再生延迟所致。 然而，与周围神经相关的神经性疼痛的持续性质表明： 周围神经固有的因素和/或受体可能有助于长期周围神经 敏化。该提案的目的是检查潜在的细胞和分子机制 通过研究炎症相关的促痛因子的产生来观察外周敏化 可以直接使感觉神经纤维和细胞体敏感。我们将确定是否患有慢性皮肤病 局灶性神经脱髓鞘动物表现出的痛觉过敏与神经脱髓鞘的程度相关。 周围神经系统中激活的细胞类型的炎症反应及其产生的结果 外周源性促炎介质 TNFot、IL-1P 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/或其各自的受体。蜂窝式 来源，炎症介质及其受体是未来药物治疗的潜在目标。 验证来自已鉴定细胞的促炎介质的药物作用可能是 通过检测转录因子 NFvcB 的激活状态来完成，该因子是 炎症介质的调节。炎症性脱髓鞘模型的组合 利用这些技术对疾病进行研究提供了前所未有的能力来研究疾病的潜在影响 细胞因子/趋化因子对啮齿动物皮肤痛觉过敏的影响。这些行为、细胞和生物化学 观察将直接推进我们对神经性疼痛细胞基础的基本认识 伴随着格林-巴利综合征和慢性炎症疼痛过程。