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: 7596188
• 负责人: FLETCHER A WHITE
• 金额: $ 10.13万
• 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 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596188
• 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; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Lead; Lesion; Link; Lysophosphatidylcholines; Maintenance; Mechanical Stimulation; 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; fiber cell; human NOS2A protein; immunocytochemistry; inhibitor/antagonist; injured; insight; macrophage; nerve injury; neuronal cell body; neuropathology; neurotrophic factor; pain behavior; painful neuropathy; programs; protein degradation; pyrrolidine dithiocarbamate; receptor; relating to nervous system; release factor; research study; response; sciatic nerve; 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.

受伤神经中的炎症反应可能是一代人中的关键因素， 维持炎症性脱髓鞘疾病（例如Guillain-Barre'S综合征）的神经性疼痛。 神经性疼痛是患有Guillain-Barre急性阶段的个体的共同特征 综合征（占患者的89％以上）和从Guillain-Barre综合征的急性阶段恢复（即 外围轴突的再髓式）不能减轻疼痛。实际上，残留的神经病影响很大 和中型的骨髓纤维在Guillain-Barre'S综合征的急性发作后很长时间耐力 大约一半的测试患者。报告的神经病包括所需阈值的增加 除了神经性疼痛外，还可以进行振动和冷感觉。振动的积极感觉症状 寒冷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 外周神经固有的因素和/或受体可能有助于长期外围 致敏。该提案的目的是检查依据的细胞和分子机制 通过研究与炎症相关的促核因子的产生，这些因素的周围敏化。 可以直接使感觉神经纤维和细胞体敏感。我们将确定是否慢性皮肤 受到局灶性神经脱髓鞘的动物表现出的痛觉过敏与 周围神经系统中激活的细胞类型的炎症反应和结果产生 外围衍生的促炎性介体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。 验证鉴定细胞的促炎性介质的药物效应可能是 通过分析转录因子NFVCB的激活状态，这是至关重要的 调节炎症介质。这种炎症性脱髓鞘模型的组合 这些技术的疾病提供了研究的前所未有的能力来研究的潜在影响 啮齿动物皮肤痛觉过敏的细胞因子/趋化因子。这些行为，细胞和生化 观察将直接将我们的基本见解转化为神经性疼痛的细胞基础， 伴随Guillain-Barre'S综合征和慢性炎症性疼痛过程。