Chemokine signaling in the transition from acute to chronic pain

从急性疼痛到慢性疼痛转变中的趋化因子信号传导

• 批准号: 8634938
• 负责人: FLETCHER A WHITE
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634938
• 关键词: AMD3100; Acute; Acute Pain; Adverse effects; Affect; Afferent Neurons; Analgesics; Animals; Antibodies; Anxiety; Area; Behavioral; Behavioral Assay; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Calcium; Cells; Chimeric Proteins; Chronic; Clinical; Data; Development; Disease; Exhibits; FDA approved; Fright; Functional disorder; Goals; Hippocampus (Brain); Inflammatory; Injury; Knock-out; Lead; Learning; Life; Ligands; Link; Location; Maintenance; Mediating; Memory; Mental Depression; Methods; Modeling; Modification; Molecular; Motor Activity; Mus; Nature; Nerve; Nervous System Trauma; Nervous system structure; Neuroglia; Neurons; Nociception; Pain; Pain Disorder; Pain Threshold; Pathway interactions; Peripheral nerve injury; Phenotype; Physicians; Population; Production; Protocols documentation; Quality of life; Rattus; Reagent; Receptor Signaling; Regulation; Reporter; Research; Rodent; Rodent Model; Role; Signal Transduction; Societies; Sodium; Spinal Cord; Spinal Ganglia; Stromal Cell-Derived Factor 1; Structure of tibial nerve; Substance abuse problem; Syndrome; Tactile Hyperalgesias; Testing; Therapeutic; Time; Transcript; Transgenic Mice; Transgenic Organisms; Veterans; Vulnerable Populations; Work; behavior change; chemokine; chemokine receptor; chronic neuropathic pain; chronic pain; cytokine; density; design; effective therapy; experience; injured; insight; interest; migration; nerve injury; neuronal excitability; new therapeutic target; novel; pain behavior; painful neuropathy; public health relevance; receptor; research study; tool; voltage; voltage clamp

The goal of this proposal is to demonstrate the importance of the chemokine/chemokine receptor signaling by stromal derived factor 1 alpha (SDF1; also known as CXCL12) and its cognate receptor CXCR4 in rodent models of neuropathic pain. Dysregulated expression chemokine receptors have been linked to hyperexcitability of dorsal root ganglia (DRG) neurons which underlies peripherally-originated neuropathic pain and constitutes a large number of neuropathic pain disorders. The studies described in this application are designed to fill the gap in our understanding of how nerve injury-induced excitatory changes in SDF1/CXCR4 signaling contribute to the persistence of chronic neuropathic pain. Our preliminary data shows that CXCR4 is absent from sensory neurons in the DRG and are generally unresponsive to SDF1. Studies in our lab have shown that injury substantially enhances both levels of CXCR4 transcripts in DRG and sensory neuron expression of CXCR4 in transgenic reporter mice. Further evidence suggests that this injury-mediated modulation of CXCR4 may also contribute to altered neuronal hyperexcitability. In this proposal, we will carry out studies of injury-mediated effects on pain thresholds and hyperexcitability at the cellular level in DRG neurons using the FDA-approved highly specific CXCR4 receptor antagonist to test the hypotheses that: i) Block of CXCR4 in DRG neurons derived from injured rodents ameliorates pain behavior; ii) Injury alters calcium or sodium currents in CXCR4 responsive nociceptive DRG neurons; iii) Modulation of SDF1/CXCR4 signaling may serve as a molecular switch to a chronic pain state. We will also use molecular and immunological methods, and voltage-clamp and current-clamp recordings to: iv) Assess injury-mediated effects on altered regulation of expression and modulation of CXCR4; and v) Correlate changes at the molecular and cellular levels in injured and adjacent, uninjured DRG neurons to changes in pain thresholds.

该提案的目的是证明趋化因子/趋化因子的重要性 基质衍生因子 1 α（SDF1；也称为 CXCL12）及其受体信号传导 神经性疼痛啮齿动物模型中的同源受体 CXCR4。表达失调 趋化因子受体与背根神经节 (DRG) 神经元的过度兴奋有关 它是外周源性神经病理性疼痛的基础，并构成大量 神经性疼痛疾病。本申请中描述的研究旨在填补空白 帮助我们了解神经损伤如何引起 SDF1/CXCR4 信号传导的兴奋性变化 导致慢性神经性疼痛的持续存在。 我们的初步数据表明 CXCR4 在 DRG 的感觉神经元中缺失，并且 通常对 SDF1 无反应。我们实验室的研究表明，伤害显着 增强 DRG 中 CXCR4 转录物的水平和 CXCR4 感觉神经元的表达 在转基因报告小鼠中。进一步的证据表明，这种损伤介导的调节 CXCR4 也可能导致神经元过度兴奋性改变。在这个提案中，我们将 损伤介导的对疼痛阈值和细胞过度兴奋性影响的研究 使用 FDA 批准的高度特异性 CXCR4 受体拮抗剂来提高 DRG 神经元的水平 检验以下假设： i) 阻断源自受伤啮齿动物的 DRG 神经元中的 CXCR4 可改善疼痛行为； ii) 损伤改变CXCR4反应性伤害性DRG神经元中的钙或钠电流； iii) SDF1/CXCR4信号传导的调节可以作为慢性疼痛的分子开关 状态。 我们还将使用分子和免疫学方法，以及电压钳和电流钳 录音至： iv) 评估损伤介导的表达调节和调节改变的影响 CXCR4；和 v) 关联受损和邻近未受损 DRG 中分子和细胞水平的变化 神经元来改变疼痛阈值。