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.

该建议的目的是证明趋化因子/趋化因子的重要性 基质衍生因子1α（SDF1;也称为CXCL12）的受体信号传导及其 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（DRG）神经元的过度兴奋性有关 这是外围原始神经性疼痛的基础，并构成了大量 神经性疼痛障碍。本应用程序中描述的研究旨在填补空白 在我们了解神经损伤引起的SDF1/CXCR4信号传导中的兴奋性变化时 有助于慢性神经性疼痛的持久性。 我们的初步数据表明，DRG中的感觉神经元不存在CXCR4，并且是 通常对SDF1无反应。我们实验室的研究表明受伤大大 增强了DRG中的CXCR4转录物和CXCR4的感觉神经元表达的两个水平 在转基因记者小鼠中。进一步的证据表明，这种伤害介导的调节 CXCR4也可能导致神经元过度兴奋性的改变。在此提案中，我们将携带 研究损伤介导的对疼痛阈值和细胞过度兴奋性的影响的研究 使用FDA批准的高度特异性CXCR4受体拮抗剂到DRG神经元中的水平 测试以下假设： i）源自受伤的啮齿动物的DRG神经元中的CXCR4块可以缓解疼痛行为； ii）损伤改变了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用作分子转换为慢性疼痛 状态。 我们还将使用分子和免疫学方法，电压钳和电流钳 记录到： iv）评估损伤介导的对表达调节和调节调节的影响 cxcr4;和 v）在受伤和邻近的，未受伤的DRG中，在分子和细胞水平上的变化相关 疼痛阈值变化的神经元。