Chemokine signaling in the transition from acute to chronic pain

这项提议的目标是证明趋化因子/趋化因子的重要性。 基质衍生因子1α(SDF1；也称为CXCL12)及其受体信号转导 神经病理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 它是外周起源的神经性疼痛的基础，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这一空白 在我们对神经损伤如何诱导SDF1/CXCR4信号的兴奋性变化的理解中 有助于慢性神经病理性疼痛的持久性。 我们的初步数据显示，CXCR4在背根节的感觉神经元中缺失，而 通常对SDF1没有反应。我们实验室的研究表明，伤害实质上 增强DRG中CXCR4转录本和感觉神经元CXCR4的表达水平 在转基因报告鼠中。进一步的证据表明，这种损伤介导的调节 CXCR4也可能参与改变神经元的超兴奋性。在这项提案中，我们将进行 损伤对细胞痛阈值和超兴奋性影响的研究 FDA批准的高度特异性CXCR4受体拮抗剂在DRG神经元中的水平 测试以下假设： I)阻断损伤啮齿动物DRG神经元中的CXCR4可改善疼痛行为； (Ii)损伤改变CXCR4反应的伤害性DRG神经元的钙或钠电流； III)SDF1/CXCR4信号的调节可能作为慢性疼痛的分子开关 州政府。 我们还将使用分子和免疫学方法，以及电压钳和电流钳 录制至： 四)评估损伤对基因表达的调节和调节的影响 CXCR4；以及 V)受损和邻近未受伤的背根节分子和细胞水平的相关变化 神经元对痛阈值的变化的反应。

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.