Molecular Mechanism of Brain Regulation of Chronic Pain

大脑调节慢性疼痛的分子机制

• 批准号: 10349433
• 负责人: MICHAEL X ZHU
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349433
• 关键词: AMPA Receptors; ASIC channel; Ablation; Acids; Adverse effects; Affect; Affective; Animals; Anterior; Area; Behavior assessment; Behavioral Assay; Binding; Biochemical; Biochemistry; Biological; Brain; Brain region; Cells; Cellular biology; Chemicals; China; Chinese; Clinical; Development; Diffusion; Electrophysiology (science); Ethylmaleimide; Fiber; Genes; Goals; Hyperalgesia; Hypersensitivity; In Situ; Inflammation; Inflammatory; Injury; Ion Channel; Ions; Laboratories; Lateral; Lead; Long-Term Potentiation; Maintenance; Mechanical Stimulation; Medical; Membrane; Molecular; Molecular and Cellular Biology; Motivation; N-ethylmaleimide-sensitive protein; Names; Neuraxis; Neurons; Nociception; Non-Steroidal Anti-Inflammatory Agents; Opioid; Pain; Pain management; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Postsynaptic Membrane; Prosencephalon; Protein Isoforms; Recycling; Regulation; Research; Resolution; Role; Sensory; Stimulus; Structure; Surface; Synapses; Synaptic plasticity; Technical Expertise; Techniques; Testing; abuse liability; behavioral study; brain research; central pain; chronic pain; chronic pain management; cingulate cortex; excitatory neuron; experience; extracellular; imaging approach; inflammatory pain; inhibitor; innovation; mechanical allodynia; mouse model; nerve injury; novel therapeutics; optogenetics; pain behavior; pain chronification; pain model; pain perception; pain processing; pain sensation; painful neuropathy; protein protein interaction; receptor; response; side effect; spared nerve; trafficking

PROJECT SUMMARY Chronic pain is debilitating medical problem that affects millions of people. However, current clinical therapy relying on opioids and non-steroidal anti-inflammatory drugs has limited efficacy because of severe adverse effects and abuse potential. To overcome these limitations, more in-depth illustration of the mechanism that underlies the development and maintenance of chronic pain will be extremely helpful. Pain perception consists of both peripheral and central components. While the peripheral mechanisms of pain have been well studied, our current understanding of the central mechanism of pain perception, especially with respect to chronic pain, remains rather limited. The current project focuses on the mechanism by which anterior cingulate cortex (ACC) of the brain participates in pain perception. It has been well-established that synaptic plasticity in ACC represents one of the most critical mechanisms underlying the transition of pain from acute to chronic. Using mouse models of chronic pain induced by peripheral inflammatory and spared nerve injury, the research team has obtained strong evidence that acid-sensing ion channel isoform 1a (ASIC1a) plays a pivotal role in both the development and maintenance of chronic pain. Not only did ACC neuron specific ablation of ASIC1a gene mitigated inflammatory hyperalgesia and mechanical allodynia, but in situ pharmacological inhibition of ASIC1a at ACC also quickly reversed the pre-established pain hypersensitivity. More intriguingly, in situ focal application of an ASIC1a activator at ACC enhanced sensitivity to peripheral thermal and mechanical stimulation within 10 minutes in the absence of peripheral inflammation or injury, indicating a crucial role of ACC ASIC1a activity in pain processing. The current project aims to elucidate the mechanism by which ACC ASIC1a regulates central pain processing at molecular, cellular and functional levels. The central hypothesis is that in ACC excitatory neurons that receive persistent nociceptive inputs, ASIC1a, in an ion conduction-independent manner, facilitates cingulate long-term potentiation through promoting forward trafficking of AMPA receptors. The enhanced synaptic efficacy in turn leads to altered sensitivity and reactivity of the pain pathways. The two specific aims are to define molecular underpinnings of ASIC1a regulation of AMPAR trafficking during the course of LTP induction and expression in ACC excitatory neurons (AIM 1) and illustrate functional relevance of molecular interactions that control AMPAR trafficking in cingulate LTP and chronic pain (AIM 2). The collaborative project will combine the unique strengths of the two laboratories in biochemical and cell biological analysis (US lab) and electrophysiological and behavioral study of plasticity and pain (China lab) to accomplish the goals. The project will greatly enhance our understanding on mechanism of ASIC1a regulation of synaptic plasticity, especially as it relates to pain hypersensitivity through enhancing synaptic efficacy at supraspinal levels, and shed new lights on more effective ways to treat chronic pain with minimal side effects.

项目概要 慢性疼痛是一种影响数百万人的衰弱性医疗问题。然而，目前临床 依赖阿片类药物和非甾体抗炎药的治疗效果有限，因为严重的 不良影响和滥用可能性。为了克服这些限制，更深入地说明 慢性疼痛发生和维持的机制将非常有帮助。疼痛 知觉由外围部分和中枢部分组成。虽然疼痛的外周机制 经过充分研究，我们目前对疼痛感知的中心机制的理解，特别是 就慢性疼痛而言，仍然相当有限。当前的项目重点关注以下机制： 大脑的前扣带皮层（ACC）参与疼痛感知。已经确定的是 ACC 中的突触可塑性是疼痛转变的最关键机制之一 从急性到慢性。使用由周围炎症引起的慢性疼痛的小鼠模型并幸免 神经损伤后，研究小组获得了有力的证据表明酸敏感离子通道亚型1a (ASIC1a) 在慢性疼痛的发生和维持中发挥着关键作用。不仅是ACC ASIC1a 基因的神经元特异性消融减轻了炎症性痛觉过敏和机械性异常性疼痛，但是 ACC 处 ASIC1a 的原位药理学抑制也迅速逆转了预先建立的疼痛 超敏反应。更有趣的是，在 ACC 处原位聚焦应用 ASIC1a 激活剂增强了 在没有外周刺激的情况下 10 分钟内对外周热和机械刺激的敏感性 炎症或损伤，表明 ACC ASIC1a 活性在疼痛处理中发挥着至关重要的作用。目前的 项目旨在阐明 ACC ASIC1a 调节中枢疼痛处理的机制 分子、细胞和功能水平。核心假设是 ACC 兴奋性神经元 接收持续的伤害性输入，ASIC1a，以离子传导独立的方式，促进 通过促进 AMPA 受体的前向运输来增强扣带皮层的长期增强作用。增强型 突触功效反过来会导致疼痛通路的敏感性和反应性改变。两个具体目标 旨在定义 LTP 过程中 ASIC1a 调节 AMPAR 运输的分子基础 ACC 兴奋性神经元 (AIM 1) 中的诱导和表达，并说明分子的功能相关性 控制扣带 LTP 和慢性疼痛中 AMPAR 运输的相互作用 (AIM 2)。协作式 项目将结合两个实验室在生化和细胞生物学分析方面的独特优势 （美国实验室）以及可塑性和疼痛的电生理学和行为研究（中国实验室）来完成 目标。该项目将极大地增进我们对ASIC1a调节突触机制的理解 可塑性，特别是因为它通过增强脊髓上的突触功效与疼痛过敏有关 水平，并为治疗慢性疼痛且副作用最小的更有效方法提供了新的线索。