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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要慢性疼痛是导致长期残疾的最常见原因，估计有 20.4% 的美国成年人患有慢性疼痛 2016 年慢性疼痛以及每年估计 5600 亿美元的直接医疗费用、生产力损失和尽管有如此巨大的影响，但针对疼痛和其他疾病的治疗选择还不够。随着时间的推移，确实可以改善患者状况的影响会逐渐减弱。此外，压力引起的心理影响也会减弱。焦虑、抑郁和疼痛灾难化等疾病与预后不良有关患有疼痛疾病的人需要开发疼痛研究的替代方法来解决这个问题。将精力集中在影响机械过程的更广泛的神经系统上。更具体地说，研究与疼痛相关的机制可能是一种可行的新方法。通过压力进行稳态疼痛处理将有助于分离慢性疼痛的神经生物学基础在这里，我们重点关注作为压力和疼痛处理纽带的蓝斑去甲肾上腺素系统。在本提案中，我们将描述 LC-NE 系统在调节应激引起的变化中的作用我们追求的 LC-NE 系统是蜂窝、电路和网络层面的伤害感受的关键组件。我们将通过一系列实验来检验压力影响伤害性输出的过程。目标 1 将检验以下假设：在处理外部物质时仅需要 LC-NE 活性。目标 2 将研究 LC-NE 末端的假设。中缝背核（DRN）的活动是应激诱导的更广泛机制中的必要步骤具体来说，我们提出了实验来确定 LC-DRN 电路激活是否有效应激暴露后对有害刺激的反应增强，以及 α1 肾上腺素能受体是否在 DRN 是应激诱导的抗伤害作用所必需的。该结果将有助于更好地理解 LC 是如何发挥作用的。 NE 系统活动在压力和疼痛期间都会发挥作用，以引发压力诱导的抗伤害作用。奖学金将为我提供细胞类型选择性体内光遗传学、体内纤维方面的强化科学培训光度测定、行为药理学和免疫组织化学多种实验的结合。方法提供了卓越的培训潜力，并辅以出色的指导承诺华盛顿大学教师和外部合作者的帮助将帮助我实现成为一位独立的学术和创业科学家。