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.

项目摘要 慢性疼痛正在使影响数百万人的医学问题使人衰弱。但是，目前的临床 依赖阿片类药物和非甾体类抗炎药的治疗具有有限的疗效 不利影响和滥用潜力。为了克服这些局限性，更深入的例证 基于慢性疼痛发展和维持的机制将非常有帮助。疼痛 感知包括外围和中央组成部分。而疼痛的外围机制 对我们目前对疼痛感知的中心机制的理解进行了充分的研究，尤其是 关于慢性疼痛，仍然相当有限。当前项目的重点是 大脑的前扣带回皮层（ACC）参与疼痛感。已经确定了 ACC中的突触可塑性代表了疼痛过渡的最关键机制之一 从急性到慢性。使用外周炎症引起的慢性疼痛的小鼠模型并保留 神经损伤，研究小组获得了有力的证据表明酸性离子通道同工型1a （ASIC1A）在慢性疼痛的发育和维持中起关键作用。不仅ACC ASIC1A基因的神经元特异性消融减轻炎症性痛觉过敏和机械性异常，但 ACC ACIC1A的原位药理抑制也迅速扭转了预先建立的疼痛 高敏性。更有趣的是，ACC ASIC1A激活剂的原位焦点应用 在没有周围的情况下，在10分钟内对外围热和机械刺激的敏感性 炎症或损伤，表明ACC ASIC1A活性在疼痛处理中起着至关重要的作用。电流 项目旨在阐明ACC ASIC1A调节中心疼痛处理的机制 分子，细胞和功能水平。中心假设是在ACC兴奋性神经元中 接收持续的伤害性输入，ASIC1A，以离子传导与独立的方式接收，促进 通过促进AMPA受体的前向运输来扣留长期增强。增强 突触功效反过来导致疼痛途径的灵敏度和反应性改变。两个具体目标 定义了在LTP过程中ASIC1A调节ASIC1A调节的分子基础 ACC兴奋性神经元中的诱导和表达（AIM 1），并说明了分子的功能相关性 控制AMPAR运输的相互作用在扣带回LTP和慢性疼痛中（AIM 2）。协作 项目将在生化和细胞生物学分析中结合两个实验室的独特优势 （美国实验室）以及可塑性和疼痛（中国实验室）的电生理学和行为研究 目标。该项目将极大地增强我们对ASIC1A突触调节机制的理解 可塑性，尤其是通过增强脊柱上的突触功效而与疼痛的超敏反应有关 水平，并以最小的副作用来治疗慢性疼痛的更有效的方法为新的灯光开了新的灯光。