Validation of Targeting Macrophage-Mediated Events in the DRG to Alleviate Chronic Spinal Cord Injury Pain

项目摘要 脊髓损伤（SCI）损害感觉传递，导致慢性神经性疼痛。慢性 疼痛折磨着1亿多美国人，给美国医疗保健系统造成了巨大的负担， 根据医学研究所最近的一份报告，尽管我们对 作为慢性疼痛发展基础的分子基础已经改善，可用的治疗方法提供有限的 救灾在拟议的行政补充，我们将检查外周免疫和炎症反应。 SCI继发性炎症反应是一系列时序性事件--急性、短暂的炎症反应， 趋化因子，随后是单核细胞/巨噬细胞的募集和炎症环境的产生， 脊髓中的损伤部位，但也包括背根神经节中的初级伤害感受器周围。这些事件发生在 神经性疼痛的发展。我们资助的R 01研究表明，在SCI后的慢性时间点，巨噬细胞 存在于背根神经节中与神经性疼痛相关。我们将扩大目前资助的实验， 进行实验以更好地理解1）是否浸润背根的巨噬细胞的表型 神经节与SCI后长期存在的神经节不同; 2）巨噬细胞表型的操纵如何影响 伤害感受器活动和疼痛发展。此外，该应用程序的很大一部分用于严格验证 巨噬细胞作为未来干预目标的潜力。建议的实验包括：1）多个 动物种属，2）纳入异常疼痛行为的几项试验，3）考虑并测量性别作为潜在的 生物变量，和4）注意到巨噬细胞操纵对其他功能的脱靶效应的可能性 比如运动和痉挛。了解这些免疫细胞的时间反应以及它们如何影响 伤害感受器活性和疼痛行为将指导未来的努力，以优化SCI引起的疼痛的治疗。

PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission leads to chronic, debilitating neuropathic pain. Chronic pain afflicts over 100 million Americans and creates an enormous burden on US health care systems, costing over half a trillion dollars annually according to a recent report from the Institute of Medicine. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. In the proposed administrative supplement, we will examine the peripheral immune and inflammatory response. Secondary inflammation in response to SCI is a series of temporally ordered events- an acute, transient upregulation of chemokines, followed by the recruitment of monocytes/ macrophages and generation of an inflammatory environment at the lesion site in the spinal cord, but also surrounding primary nociceptors in the dorsal root ganglia. These events precede neuropathic pain development. Work on our funded R01 has shown that at chronic time points after SCI, macrophage presence in the dorsal root ganglia correlates with neuropathic pain. We will extend the currently funded experiments by conducting experiments to better understand 1) whether the phenotype of macrophages that infiltrate the dorsal root ganglia is different than those that persist chronically after SCI and 2) how manipulation of macrophage phenotype affects nociceptor activity and pain development. Moreover, a large portion of this application is dedicated to rigorous validation of the potential of the macrophage as a target for future interventions. The proposed experiments include: 1) multiple species of animals, 2) inclusion of several tests for aberrant pain behavior, 3) consider and measure sex as a potential biological variable, and 4) attend to the potential of off-target effects of macrophage manipulation on other functional outcomes like locomotion and spasticity. Understanding the temporal response of these immune cells and how they affect nociceptor activity and pain behavior will guide future efforts to optimize the treatment of SCI-induced pain.