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: 10315525
• 负责人: Makenzie Norris
• 金额: $ 3.39万
• 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/10315525
• 关键词: Dissecting; locus; coeruleus; contributions; stress

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.

项目总结/摘要 慢性疼痛是长期残疾的最常见原因，估计有20.4%的美国成年人患有慢性疼痛。 2016年，慢性疼痛和估计每年5600亿美元的直接医疗费用，生产力损失， 残疾人项目。尽管有这种巨大的影响，但疼痛的治疗选择不足， 那些确实能改善病人状况的药物随着时间的推移会变得不那么有效。此外，压力引起的心理 诸如焦虑、抑郁和疼痛灾难化的疾病与预后不良有关， 疼痛的人。有必要开发疼痛研究的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 可能是一种可行的新方法。更具体地说， 内稳态疼痛处理被压力改变将有助于分离慢性疼痛的神经生物学基础。 痛苦在这里，我们专注于蓝斑去甲肾上腺素系统作为压力和疼痛处理的联系。 在本提案中，我们将描述LC-NE系统在调节应激诱导的变化中的作用， 细胞、电路和网络层面的伤害感受。我们假设LC-NE系统是一个关键组成部分， 压力影响伤害性输出的过程。我们将在一系列实验中验证这一假设。 目标。目的1将检验LC-NE活性仅在外部信号处理过程中需要的假设。 最终导致抗伤害效应。目的2将研究LC-NE末端 中缝背核（DRN）的活动是压力诱导的更广泛机制中的必要步骤。 抗伤害感受具体地说，我们已经提出了实验，以确定是否LC-DRN电路激活， 在应激暴露后对伤害性刺激的反应中增强，以及在应激暴露后， DRN是应激诱导的抗伤害感受所必需的。结果将提供一个更好的了解如何LC- NE系统的活动在应激和疼痛过程中被利用，以引起应激诱导的抗伤害感受。这 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 光度测定法、行为药理学和免疫组织化学。结合不同的实验 方法提供了良好的培训潜力，并与杰出的导师承诺相结合 来自华盛顿大学的教师和外部合作者将帮助我实现我的职业目标， 独立的学术和创业科学家。