Mechanisms of Central Sensitization

中枢敏化机制

• 批准号: 10188656
• 负责人: Robert W Gereau
• 金额: $ 51.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188656
• 关键词: Acute; Acute Pain; Address; Affect; American; Amygdaloid structure; Analgesics; Anxiety; Award; Behavior; Behavioral Genetics; Bilateral; Brain; Brain Stem; Cell Nucleus; Chromosome Mapping; Clinical; Data; Development; Disease; Drug usage; Electrophysiology (science); Extracellular Signal Regulated Kinases; Funding; Future; GRM5 gene; Generations; Genetic; Genetic Markers; Goals; Health; Healthcare; Hypersensitivity; Image; Inflammatory; Injury; Institute of Medicine (U.S.); Intervention; Laboratories; Left; Mediating; Mediator of activation protein; Metabotropic Glutamate Receptors; Modeling; Modernization; Molecular; Monitor; National Institute of Neurological Disorders and Stroke; Nervous system structure; Neurons; Neuropathy; Nociception; Opioid; Output; Pain; Pain management; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Population; Price; Property; Publishing; Reporting; Research; Sensory Process; Series; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Techniques; Technology; Testing; Time; Touch sensation; Viral; Vision; Wireless Technology; Work; anxiety-related behavior; central pain; central sensitization; chronic pain; clinical pain; comorbidity; design; effective therapy; genetic signature; in vivo; in vivo calcium imaging; inflammatory pain; insight; microendoscope; negative affect; neurochemistry; neuroregulation; new therapeutic target; nociceptive response; novel; optogenetics; pain perception; pain processing; pain reduction; pain relief; painful neuropathy; parabrachial nucleus; relating to nervous system; sensor; side effect; therapeutic target; transcriptomics; translation to humans; two-photon

Abstract Chronic pain represents an immense clinical problem, with over 100 million Americans afflicted and an annual price tag exceeding half a trillion dollars, according to a recent report from the Institute of Medicine. Studies in our lab are designed to identify molecular, cellular, and circuit mechanisms of sensitization in pain pathways with the goal of identifying novel targets for analgesic intervention. Studies performed in our lab previously identified a critical signaling cascade in neurons of the central nucleus of the amygdala (CeA) that underlies central pain sensitization. This pathway is initiated by metabotropic glutamate receptor subtype 5 (mGlu5) activation of extracellular signal-regulated kinase/ERK signaling, leading to increased firing of CeA neurons. This increase in excitability likely contributes to central sensitization associated with persistent pain. Our prior work, and that of several other groups, suggests that neurons in the CeA represent a critical node of neuromodulation underlying the development of chronic pain. An important finding from our prior studies was that this maladaptive plasticity in the CeA leading to persistent pain sensitization is specific to the right hemisphere. That is, no matter the sight of the injury, plasticity in the right (and not left) CeA was responsible for bilateral pain hypersensitivity. Furthermore, manipulation of neural activity only in the right CeA was found to produce bilateral pain sensitization. The mechanisms generating this hemispheric lateralization are completely unknown. In the present application, we will conduct a series of studies aimed at understanding the circuit context of CeA neurons that are activated by acute pain sensitization. We will perform studies aimed at identifying critical inputs, the type of plasticity that occurs at these synapses, and the major outputs of pain-responsive CeA neurons. We will test whether CeA neurons activated in the context of pain sensitization are necessary and sufficient for the development of pain sensitization, ongoing pain and comorbid disorders. By specifically targeting pain- activated neurons in this study, we may be able to determine if they possess unique neurochemical properties that represent novel therapeutic targets, or genetic signatures that would enable future studies to more precisely determine their function. In vivo 2-photon imaging and microendoscope cameras will be used to monitor activity of these neurons using genetically-encoded Ca2+ sensors, over days to weeks, to determine how the properties of these neurons change during the transition from acute to persistent pain. We will ask whether the population of neurons responsive to heat, cold, or touch change over time, and whether altered activity of these neurons in persistent pain conditions can be normalized using treatments that reduce pain or comorbid anxiety. These studies employ a host of modern techniques including advanced viral tracing, genetic mapping, in vivo calcium imaging, and optogenetic approaches, together with technologies developed in our lab for wireless optogenetic studies to address these important questions.

摘要 慢性疼痛是一个巨大的临床问题，超过1亿美国人患有慢性疼痛， 根据医学研究所最近的一份报告，每年的价格标签超过5000亿美元。 我们实验室的研究旨在确定致敏的分子、细胞和电路机制。 疼痛通路，目的是确定止痛干预的新靶点。在以下方面进行的研究 我们的实验室之前在杏仁中央核的神经元中发现了一个关键的信号级联反应 (CEA)，这是中枢疼痛敏化的基础。这一途径是由代谢性谷氨酸启动的 受体亚型5(MGlu5)激活细胞外信号调节的激酶/ERK信号，导致 CEA神经元放电增加。这种兴奋性的增加可能有助于中枢敏感化 与持续性疼痛有关。我们之前的工作以及其他几个小组的工作表明，神经元 在CEA中，代表了慢性疼痛发生的神经调节的关键节点。一个 我们先前研究的重要发现是，CEA中的这种不适应可塑性导致 持续性疼痛敏感化是右脑特有的。也就是说，无论伤情如何， 右侧(而非左侧)CEA的可塑性是双侧疼痛过敏的原因。此外， 仅操纵右侧CEA的神经活动可产生双侧疼痛敏感化。这个 产生这种半球偏侧化的机制是完全未知的。在现在 应用，我们将进行一系列研究，旨在了解CEA神经元的电路背景 都是由急性疼痛敏感化激活的。我们将进行研究，以确定关键投入、类型 这些突触的可塑性，以及痛反应CEA神经元的主要输出。我们会 测试在疼痛敏化的背景下激活的CEA神经元是否对 发展为疼痛敏感化、持续疼痛和共病障碍。通过专门针对疼痛- 在这项研究中，我们可能能够确定它们是否具有独特的神经化学物质 代表新的治疗靶点的特性，或使未来研究能够 更准确地确定它们的功能。在体内，双光子成像和显微内窥镜相机将 用来监测这些神经元的活动，使用遗传编码的钙传感器，在几天到几周内，以 确定这些神经元的特性在从急性疼痛到持续性疼痛的转变过程中是如何变化的。我们 会问，对热、冷或触摸反应的神经元数量是否会随着时间的推移而变化，以及 在持续性疼痛条件下，这些神经元活动的改变可以通过减少 疼痛或共病焦虑。这些研究使用了许多现代技术，包括先进的病毒 示踪、基因图谱、体内钙成像和光遗传学方法及其技术 我们实验室为解决这些重要问题而开发的无线光遗传学研究。