The Role of the Complement System in Spinal Mechanisms of Chronic Pain

补体系统在慢性疼痛脊柱机制中的作用

• 批准号: 10643985
• 负责人: Yuriy M Usachev
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643985
• 关键词: Action Potentials; Affect; American; Analgesics; Animal Model; Behavior assessment; Biochemical Reaction; Biological Response Modifiers; Brain; Brain Diseases; C5a anaphylatoxin receptor; Classification; Clinical; Collaborations; Complement; Complement 5a; Country; Data; Development; Drug Targeting; Electrophysiology (science); Environment; Etiology; Genetic; Host Defense; Human Resources; Hyperalgesia; Hypersensitivity; Image; Immune system; Inflammatory; Infrastructure; Knock-out; Label; Measures; Mechanics; Microglia; Modeling; Natural Immunity; Neurons; Neuropathy; Nociception; Nociceptors; Output; Pain; Pain Research; Pain management; Pathogenesis; Pathway interactions; Patients; Persistent pain; Play; Posterior Horn Cells; Preparation; Production; Receptor Signaling; Regulation; Research; Role; Scientist; Signal Transduction; Spinal; Spinal Cord; Structure; Testing; Tissues; Training; Ukraine; Up-Regulation; Vertebral column; allodynia; antagonist; behavior test; behavioral pharmacology; central sensitization; chronic pain; chronic pain management; complement system; dorsal horn; efficacious treatment; improved; inflammatory pain; innovation; innovative technologies; insight; interdisciplinary approach; multi-photon; nerve damage; nerve injury; novel therapeutics; optogenetics; pain processing; painful neuropathy; patch clamp; pharmacologic; pre-clinical; prevent; receptor expression; recruit; side effect; spared nerve; spinal pathway; spontaneous pain; synergism; treatment strategy

PROJECT SUMMARY / ABSTRACT Persistent pain affects 100 million Americans and 15 million Ukrainians. The immune system critically contributes to pathogenesis of inflammatory and neuropathic pain, and precise understanding of mechanisms through which particular immune mediators contribute to sensitization of nociceptive neuronal pathways will be essential for developing more efficacious treatment strategies. The complement system is a principal component of innate immunity that contributes to host defenses via diverse mechanisms. In spite of growing evidence implicating the complement system in various chronic pain states, the underlying mechanisms are not well understood. Our main objectives for this collaborative proposal between the US and Ukrainian groups are to elucidate complement-dependent spinal mechanisms that contribute to the development of neuropathic pain, and at a broader level, to promote building and strengthening sustainable research capacity in Ukraine. Mechanical hypersensitivity and spontaneous pain are common features of neuropathic pain. The main nociceptive output pathway from the spinal cord to the brain underlying this abnormal pain processing is lamina I projection neurons (PNs) of dorsal horn (DH). Our patch-clamp recordings from these neurons using an innovative intact spinal cord preparation demonstrate abnormal regulation of spinal cord output following spared nerve injury (SNI), a common model of neuropathic pain that well reproduces many features of clinical neuropathic pain. Recent studies suggest that neuropathic pain is associated with a robust upregulation of complement effectors in the spinal cord, which ultimately leads to production of a highly active complement product, C5a. Intrathecal administration of C5a produces allodynia, whereas C5 knockout (KO) and C5a receptor (C5aR1) antagonists produce analgesic effects in animal models of neuropathic pain. Our preliminary data show that C5aR1 KO prevents mechanical hypersensitivity following SNI. C5aR1 in the DH is found primarily on microglia that is known to be activated in the DH after SNI. Moreover C5aR1 expression is increased after SNI. We will use a multidisciplinary approach including patch-clamp recordings, optogenetic stimulation and multi-photon Ca2+ imaging in innovative intact spinal cord preparation combined with behavioral pharmacology to test our central hypothesis that C5a/C5aR1 signaling plays important roles in neuropathic pain processing by impacting central sensitization via microglia-dependent signaling that enhances the output of lamina I PNs of the DH to the supraspinal structures. This proposal will provide mechanistic insight into the function of the complement system in the CNS pain processing, and may lead to the development of new analgesic drugs that target complement system. In its broader impact, this project will promote establishment of Center for Excellence in brain disorder research in Ukraine, and help attracting young Ukrainian scientists to this field, providing their training and advancing chronic pain research in this country.

项目概要/摘要 持续的疼痛影响着 1 亿美国人和 1500 万乌克兰人。免疫系统严重受损 有助于炎症和神经性疼痛的发病机制，以及对机制的精确理解 通过特定的免疫介质有助于伤害性神经元通路的敏化 对于制定更有效的治疗策略至关重要。补体系统是主要的 先天免疫的组成部分，通过多种机制有助于宿主防御。尽管不断成长 有证据表明补体系统参与各种慢性疼痛状态，其潜在机制是 不太理解。美国和乌克兰团体之间这项合作提案的主要目标 旨在阐明有助于神经病发展的补体依赖性脊柱机制 痛苦，并在更广泛的层面上，促进建设和加强乌克兰的可持续研究能力。 机械性超敏反应和自发性疼痛是神经性疼痛的常见特征。主要 从脊髓到大脑的伤害性输出通路是这种异常疼痛处理的基础 I 背角 (DH) 的投射神经元 (PN)。我们使用膜片钳记录这些神经元 创新的完整脊髓制备表明脊髓输出的异常调节 幸存神经损伤（SNI），一种常见的神经病理性疼痛模型，可以很好地再现临床的许多特征 神经性疼痛。最近的研究表明，神经性疼痛与 脊髓中的补体效应器，最终导致高活性补体的产生 产品，C5a。鞘内注射 C5a 会产生异常性疼痛，而 C5 敲除 (KO) 和 C5a 受体 (C5aR1) 拮抗剂在神经性疼痛动物模型中产生镇痛作用。我们的初步 数据显示，C5aR1 KO 可预防 SNI 后的机械过敏。 DH 中发现 C5aR1 主要针对小胶质细胞，已知小胶质细胞在 SNI 后在 DH 中被激活。此外，C5aR1 表达为 SNI 后增加。我们将使用多学科方法，包括膜片钳记录、光遗传学 创新完整脊髓制备中的刺激和多光子 Ca2+ 成像与行为相结合 药理学来检验我们的中心假设，即 C5a/C5aR1 信号在神经病理性中发挥重要作用 通过小胶质细胞依赖性信号传导影响中枢敏化来增强输出，从而进行疼痛处理 DH 的椎板 I PN 到椎上结构。该提案将提供对机制的深入了解 补体系统在中枢神经系统疼痛处理中的功能，并可能导致新的开发 以补体系统为靶点的镇痛药。就其更广泛的影响而言，该项目将促进建立 乌克兰脑部疾病研究卓越中心，并帮助吸引年轻的乌克兰科学家 这个领域，为他们提供培训并推进这个国家的慢性疼痛研究。