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.

抽象的 慢性疼痛代表了一个巨大的临床问题，超过1亿美国人遭受了苦难 根据医学研究所的最新报告，年度价格超过半万亿美元。 我们实验室的研究旨在鉴定敏化的分子，细胞和电路机制 疼痛途径的目的是确定新颖的镇痛干预目标。进行的研究进行了 我们的实验室先前鉴定了杏仁核中央核神经元中的关键信号级联 （CEA）是中央疼痛敏化的基础。该途径是由代谢性谷氨酸引发的 受体亚型5（MGLU5）激活细胞外信号调节激酶/ERK信号，导致 CEA神经元的发射增加。兴奋性的这种增加可能有助于中央敏感性 与持续的疼痛有关。我们先前的工作以及其他几个小组的工作表明神经元 在CEA中，是慢性疼痛发展的基础神经调节的关键节点。一个 我们先前研究的重要发现是，CEA中的这种不良适应性可塑性导致 持续的疼痛敏化是特定于右半球的。也就是说，无论受伤如何 右侧（不左）的可塑性是双侧疼痛超敏反应的原因。此外， 仅发现对右CEA中神经活动的操纵才能产生双侧疼痛敏化。这 产生该半球横向化的机制是完全未知的。现在 应用，我们将进行一系列研究，以了解CEA神经元的电路环境 通过急性疼痛敏化激活。我们将进行旨在识别关键输入的研究 这些突触处发生的可塑性，以及疼痛反应性CEA神经元的主要输出。我们将 测试在疼痛敏化背景下激活的CEA神经元是否需要 疼痛致敏，持续疼痛和合并症的发展。通过专门针对疼痛 活化的神经元在这项研究中，我们可以确定它们是否具有独特的神经化学 代表新的治疗靶标的特性或遗传性特征，使未来的研究能够 更精确地确定其功能。体内2光子成像和微型内脏镜摄像机将是 用于使用遗传编码的Ca2+传感器来监测这些神经元的活动，数天至数周内 确定在从急性到持续性疼痛的过渡期间这些神经元的特性如何变化。我们 会询问神经元的人群是否会随着时间的流逝而响应热，寒冷或触摸的变化，以及是否是否 这些神经元在持续性疼痛条件下的活性改变可以通过减少的治疗进行标准化 疼痛或合并焦虑。这些研究采用了许多现代技术，包括高级病毒 跟踪，基因映射，体内钙成像和光遗传学方法以及技术 在我们的实验室进行无线光遗传学研究中开发，以解决这些重要问题。