Regulation of SCI-induced pain by macrophages and exercise

项目总结 脊髓损伤(SCI)损害了感觉传递，并导致慢性、衰弱的神经病变 疼痛。慢性疼痛困扰着1亿多美国人，给美国的医疗保健带来了巨大的负担 系统，根据医学研究所最近的一份报告，每年花费超过5000亿美元。 虽然我们对慢性疼痛发生的分子基础的了解有所改善，但 现有的治疗方法只能提供有限的缓解。虽然我们的实验室和其他人已经证明了脊髓损伤后早期康复 可以防止疼痛的发展，但由于多系统的原因，人类脊髓损伤的早期康复可能是不可能的， 患有脊髓损伤的人遭受多重创伤。因此，迫切需要一种辅助疗法来帮助 那些不能参加早期康复的个人。神经病理性疼痛日益被认为是一种 神经免疫性疾病。虽然巨噬细胞被认为是慢性疼痛发展的关键调节细胞，但它是 不清楚他们的行为是煽动性的还是修复性的。本R01旨在更好地理解 巨噬细胞的激活状态如何或是否影响伤害性神经元的兴奋性和疼痛的发展 在SCI之后。我们将利用已建立的神经病理性疼痛发展和驱动的脊髓损伤模型。 损伤后康复的巨噬细胞激活状态，鞘内注射原始来源的外切体 264.7体外刺激的巨噬细胞或聚合物纳米递送系统的磷酸二酯酶4抑制剂 这是专门针对巨噬细胞的。这项提议试图了解巨噬细胞渗透的作用。 背根神经节在脊髓损伤后的发育和维持中的长期存在 慢性神经病理性疼痛。

PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission and 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. While our lab and others have shown that early post-SCI rehab can prevent pain development, early rehab in human SCI may not be possible due to the multisystem, polytraumatic injuries individuals with SCI sustain. Thus, there is a critical need for an adjuvant therapy to aid those individuals who are unable to participate in early rehab. Neuropathic pain is increasingly recognized as a neuroimmune disorder. While macrophages are regarded as key regulators of chronic pain development, it is unclear whether they are acting in an inflammatory or reparative manner. This R01 seeks to better understand how or if the activation state of macrophages influences nociceptive neuron excitability and pain development after SCI. We will utilize an established spinal cord injury model of neuropathic pain development and drive macrophage activation state by post-injury rehab, intrathecal administration of exosomes derived from Raw 264.7 macrophages stimulated in vitro or a phosphodiesterase 4 inhibitor by a polymer nanodelivery system that specifically targets macrophages. This proposal seeks to understand the role of macrophages that infiltrate the dorsal root ganglia and persist there chronically after SCI both in the development and maintenance of chronic neuropathic pain.