Regulation of SCI-induced pain by macrophages and exercise

巨噬细胞和运动对 SCI 引起的疼痛的调节

• 批准号: 10736378
• 负责人: MEGAN R DETLOFF
• 金额: $ 44.26万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736378
• 关键词: Ablation; Adjuvant Therapy; American; Analgesics; Attenuated; Cells; Chronic; Control Groups; Cyclic AMP; Data; Development; Dichloromethylene Diphosphonate; Disease; Encapsulated; Enzyme-Linked Immunosorbent Assay; Exercise; Flow Cytometry; Funding; Harvest; Healthcare Systems; Human; Hydrophobicity; Impairment; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Injections; Injury; Institute of Medicine (U.S.); Liposomes; Macrophage; Macrophage Activation; Maintenance; Measures; Modeling; Molecular; Nanodelivery; Neuroimmune; Neurons; Nociceptors; Pain; Phenotype; Physiological; Population; Prevention; Probability; Process; Rattus; Regulation; Rehabilitation therapy; Reporting; Role; Rolipram; Sensory; Serum; Spinal Ganglia; Spinal cord injury; Subgroup; System; Technology; Testing; Therapeutic; Walking; axonal sprouting; chronic neuropathic pain; chronic pain; cost; cytokine; disability; exercise rehabilitation; exosome; extracellular vesicles; improved; in vivo; inhibitor; injured; nanopolymer; nanotherapeutic; neuronal excitability; neuropathology; pain behavior; pain reduction; painful neuropathy; phosphodiesterase IV; prevent; spinal cord injury pain; transmission process

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.

项目概要 脊髓损伤 (SCI) 会损害感觉传递并导致慢性、衰弱性神经病 疼痛。慢性疼痛困扰着超过一亿美国人，给美国医疗保健造成巨大负担 根据医学研究所最近的一份报告，该系统每年花费超过 5000 亿美元。 虽然我们对慢性疼痛发展的分子基础的了解有所提高，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实验室已经表明，脊髓损伤后早期康复 可以预防疼痛的发展，由于多系统，人类 SCI 的早期康复可能是不可能的， 患有 SCI 的人会遭受多发性损伤。因此，迫切需要辅助治疗来帮助 那些无法参加早期康复的人。神经性疼痛越来越被认为是一种 神经免疫紊乱。虽然巨噬细胞被认为是慢性疼痛发展的关键调节因子，但它 尚不清楚它们是否以炎症或修复方式起作用。此 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感受神经元的兴奋性和疼痛的发展 SCI之后。我们将利用已建立的神经性疼痛发展和驱动的脊髓损伤模型 通过损伤后康复、鞘内注射源自 Raw 的外泌体来激活巨噬细胞 264.7 通过聚合物纳米递送系统体外刺激巨噬细胞或磷酸二酯酶 4 抑制剂 专门针对巨噬细胞。该提案旨在了解巨噬细胞渗透的作用 背根神经节并在 SCI 后长期存在于该处，以发展和维持 慢性神经性疼痛。

项目成果

Modelling at-level allodynia after mid-thoracic contusion in the rat.

• DOI: 10.1002/ejp.1711
• 发表时间: 2021-04
• 期刊: European journal of pain (London, England)
• 作者: Blumenthal GH;Nandakumar B;Schnider AK;Detloff MR;Ricard J;Bethea JR;Moxon KA
• 通讯作者: Moxon KA

Plasticity in Cervical Motor Circuits following Spinal Cord Injury and Rehabilitation.

• DOI: 10.3390/biology10100976
• 发表时间: 2021-09-28
• 期刊: Biology
• 影响因子: 4.2
• 作者: Walker JR;Detloff MR
• 通讯作者: Detloff MR