Chemokine signaling in the transition from acute to chronic pain

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（SDF 1;也称为CXCL 12）及其受体信号传导 同源受体CXCR 4在啮齿动物模型中的神经性疼痛。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 其是外周源性神经性疼痛的基础，并构成了大量的 神经性疼痛障碍。本申请中描述的研究旨在填补差距 在我们理解神经损伤如何诱导SDF 1/CXCR 4信号的兴奋性变化时， 导致慢性神经性疼痛的持续存在。 我们的初步数据显示，CXCR 4在DRG的感觉神经元中不存在，并且在DRG中表达。 一般对SDF 1无反应。我们实验室的研究表明， 增强DRG中CXCR 4转录物和感觉神经元CXCR 4表达水平 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， CXCR 4也可能有助于改变神经元的过度兴奋。在这份提案中，我们将 研究了损伤介导的对痛阈和细胞过度兴奋的影响， 使用FDA批准的高度特异性CXCR 4受体拮抗剂， 检验以下假设： i）阻断源自受损啮齿动物的DRG神经元中的CXCR 4改善疼痛行为; ii）损伤改变CXCR 4应答性伤害性DRG神经元中的钙或钠电流; iii）SDF 1/CXCR 4信号传导的调节可以作为慢性疼痛的分子开关 状态 我们还将采用分子生物学和免疫学的方法，以及电压钳和电流钳技术 录制到： iv）评估损伤介导的对以下改变的表达调节和调节的影响： CXCR 4;和 v）在损伤的和邻近的未损伤的DRG中在分子和细胞水平上的相关变化 神经元对疼痛阈值的变化。

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.