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.

项目总结 慢性疼痛是影响数百万人的令人衰弱的医疗问题。然而，目前的临床 依赖阿片类药物和非类固醇抗炎药的治疗因严重的 不良影响和滥用的可能性。要克服这些限制，请更深入地说明 形成和维持慢性疼痛的机制将是非常有帮助的。疼痛 知觉由外周和中枢两部分组成。而疼痛的外周机制 已经得到了很好的研究，我们目前对疼痛感知的中枢机制的理解，特别是 对于慢性疼痛，其止痛效果仍然相当有限。目前的项目重点是通过什么机制 大脑的前扣带回皮质(ACC)参与痛觉。已经有充分的证据表明 ACC的突触可塑性是痛觉转换最关键的机制之一 从急性到慢性。用小鼠外周炎性慢性疼痛模型及免疫耐受 在神经损伤方面，研究小组已经获得了强有力的证据，表明酸敏离子通道亚型1a (ASIC1a)在慢性疼痛的发生和维持中起着关键作用。不仅是Access 神经元特异性消融ASIC1a基因可减轻炎性痛觉过敏和机械性痛觉过敏，但 在ACC处原位药物抑制ASIC1a也能迅速逆转预先建立的疼痛 过敏症。更耐人寻味的是，在ACC现场聚焦应用ASIC1a激活剂的情况得到了加强 在没有外周的情况下，在10分钟内对外周的热和机械刺激敏感 炎症或损伤，表明ACC ASIC1a活性在疼痛处理中起关键作用。海流 该项目旨在阐明ACC ASIC1a调节中枢疼痛处理的机制 分子、细胞和功能水平。中心假说是在ACC兴奋性神经元中 以离子传导独立的方式接收持续的伤害性输入ASIC1a，有助于 通过促进AMPA受体的前向运输来扣带长时程增强。增强版 突触效应反过来导致痛觉通路的敏感度和反应性改变。两个具体目标 是确定ASIC1a在LTP过程中调节AMPAR运输的分子基础 ACC兴奋性神经元(AIM-1)的诱导和表达及其与功能的关系 控制扣带回LTP和慢性疼痛中AMPAR运输的相互作用(目标2)。协作 该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)和电生理和行为可塑性与疼痛研究(中国实验室)，以完成 目标。该项目将极大地提高我们对ASIC1a对突触调控机制的理解 可塑性，特别是当它通过增强脊髓上突触的效率与疼痛过敏有关时 水平，并揭示了更有效的方法来治疗慢性疼痛，副作用最小。