Dissecting locus coeruleus contributions to stress-induced antinociception

剖析蓝斑对应激诱导的抗伤害作用的贡献

• 批准号: 10532687
• 负责人: Makenzie Norris
• 金额: $ 3.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532687
• 关键词: Acute; Address; Adrenergic Antagonists; Adrenergic Receptor; Adult; Agonist; Anxiety; Behavioral; Brain; Brain region; Calcium; Data; Development; Esthesia; Faculty; Fellowship; Fiber; Goals; Hypersensitivity; Immunohistochemistry; Laboratories; Link; Literature; Mediating; Medical Care Costs; Mental Depression; Mental disorders; Mentorship; Neurobiology; Neurons; Neurosciences; Nociception; Norepinephrine; Output; Pain; Pain Research; Pain Threshold; Pain management; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Photometry; Physiological; Process; Productivity; Prognosis; Role; Scientist; Series; Serotonin; Specificity; Spinal Cord; Stimulus; Stress; Structure; System; Testing; Therapeutic; Time; Training; Universities; Washington; Work; acute stress; behavioral pharmacology; behavioral response; career; cell type; chronic pain; disability; dorsal raphe nucleus; experience; experimental study; improved; in vivo; innovation; locus ceruleus structure; monoamine; nerve supply; noradrenergic; norepinephrine system; novel; novel strategies; optogenetics; pain catastrophizing; pain inhibition; pain processing; pain reduction; pain relief; programs; receptor; response; restraint stress; stressor; theories; transmission process

Project Summary/Abstract Chronic pain is the most common cause of long-term disability with an estimated 20.4% of U.S. adults had chronic pain in 2016 and an estimated $560 billion each year in direct medical costs, lost productivity, and disability programs. Despite this immense impact, there are insufficient therapeutic options for pain and those that do improve patient conditions become less impactful over time. In addition, stress-induced psychological disorders such as anxiety, depression, and pain catastrophizing have been associated with poor prognosis in people with pain conditions. There is a need to develop alternative approaches to pain research to tackle this systemic problem. Focusing efforts on broader neuronal systems that influence the mechanistic processes associated with pain may be a viable novel approach. More specifically, investigating mechanisms by which homeostatic pain processing is altered by stress will aid in isolating neurobiological underpinnings of chronic pain. Here, we focus on the locus coeruleus norepinephrine system as a nexus of stress and pain processing. In this proposal we will characterize the role of the LC-NE system in modulating stress-induced changes to nociception at cellular, circuit, and network levels. We hypothesize the LC-NE system is a critical component to the process by which stress influences nociceptive output. We will test this hypothesis in a series of experimental aims. Aim 1 will test the hypothesis that LC-NE activity is required exclusively during the processing of an external stressor to ultimately result in an antinociceptive effect. Aim 2 will investigate the hypothesis that LC-NE terminal activity in the dorsal raphe nucleus (DRN) is a required step within the broader mechanism of stress-induced antinociception. Specifically, we have proposed experiments to determine whether LC-DRN circuit activation is potentiated in response to noxious stimuli after stress exposure and whether 1-adrenergic receptors within the DRN are required for stress-induced antinociception. The results will provide a better understanding of how LC- NE system activity is leveraged during both stress and pain to elicit stress-induced antinociception. This fellowship will provide me with intensive scientific training in cell-type selective in vivo optogenetics, in vivo fiber photometry, behavioral pharmacology, and immunohistochemistry. The combination of diverse experimental approaches provides excellent training potential and compounded with outstanding mentorship commitment from faculty at Washington University and external collaborators will help me achieve my career goal of becoming an independent academic and entrepreneurial scientist.

项目摘要/摘要 慢性疼痛是长期残疾的最常见原因，估计有20.4％的美国成年人 2016年的慢性疼痛，估计每年的直接医疗费用，生产率下降和5600亿美元 残疾计划。尽管有这种影响，但疼痛的治疗选择不足 随着时间的流逝，确实会改善患者状况的影响力降低。此外，压力引起的心理 焦虑，抑郁和疼痛等疾病与预后不良有关 患有疼痛状况的人。有必要开发替代方法来解决这个问题 系统性问题。将精力集中在影响机械过程的更广泛的神经元系统上 与疼痛相关的可能是一种可行的新方法。更具体地说，调查了该机制 压力改变了稳态疼痛处理将有助于隔离慢性的神经生物学基础 疼痛。在这里，我们将重点放在去甲肾上腺素系统的基因座，作为压力和疼痛处理的联系。 在此提案中，我们将表征LC-NE系统在调节压力引起的变化中的作用 细胞，电路和网络水平的伤害感受。我们假设LC-NE系统是对 压力影响伤害输出的过程。我们将在一系列实验中检验该假设 目标。 AIM 1将检验以下假设：外部处理过程中只需要LC-NE活动 压力源最终导致抗伤害感受效应。 AIM 2将研究LC-NE终端的假设 背侧raphe核us（DRN）的活性是应激诱导的更广泛机理的必需步骤 抗inocetion。特别是，我们提出了实验以确定LC-DRN电路激活是否为 压力暴露后对有害刺激的响应增强 DRN是压力诱导的抗伤害感受所必需的。结果将更好地了解LC- 在压力和疼痛期间，NE系统活性均具有引起压力引起的抗伤害感受。这 奖学金将为我提供细胞型选择性体内光遗传学的深入科学培训，体内纤维 光度法，行为药理学和免疫组织化学。潜水员实验的组合 方法提供了出色的培训潜力，并以出色的精明力承诺加重 来自华盛顿大学的教师和外部合作者将帮助我实现自己的职业目标 独立的学术和企业家科学家。