Identification and Validation of a Novel Central Analgesia Circuit

新型中枢镇痛回路的识别和验证

• 批准号: 10362236
• 负责人: Joseph P Mathew
• 金额: $ 208.22万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362236
• 关键词: Identification; Validation; Novel; Central; Analgesia

ABSTRACT Chronic pain is a major health problem that afflicts one third of Americans. New research that can aid the development of new pain-relieving strategies is urgently needed. Our proposal focuses on identifying and validating a new central analgesic circuit. This project is based on a highly innovative hypothesis that the strong analgesic effect of general anesthesia (GA) is in part carried out by GA-mediated activation of the endogenous analgesic circuits. In preliminary studies, we discovered that a subset of GABAergic neurons located in the central amygdala (CeA) become strongly activated and express high level of the immediate early gene Fos under GA (hereafter referred to as CeAGA neurons). Excitingly, using our recently developed activity-dependent tagging system called CANE (Capturing Activated Neuronal Ensemble), we were able to capture CeAGA neurons and discovered that activating these neurons exerted profound pain-suppressing effects in an acute pain model and a chronic orofacial neuropathic pain model. Based on these exciting preliminary results, we propose to identify and validate CeAGA neurons’ analgesic functions in multiple mouse pain models conducted in different labs (Wang and Ji, co-PI). In aim 1, we will systematically activate and silencing CeAGA analgesic neurons and test the consequences of such bi- directional manipulations on regulating the sensory-discriminative and emotional-affective aspects of pain processing in naïve mice and in several mouse models of acute and chronic pain models with cross validation between the two labs. In aim 2, using the state-of-the-art in vivo imaging technology, we will test the hypothesis that the spontaneous activities of CeAGA analgesic neurons are severely reduced in various chronic pain models compared to naïve conditions, leading to pain hypersensitivity in these models (due to the suppression of this endogenous analgesic circuit); and complimentary, we will use slice electrophysiology to examine changes in intrinsic and evoked properties of CeAGA analgesic neurons in normal and chronic pain conditions which may explain the altered in vivo activities. In aim 3, based on preliminary results showing extensive axonal projections of CeAGA to many brain areas, we will identify the critical subsets of CeAGA projection pathway(s) for their analgesic effect in different chronic pain models. We expect to identify shared common pathways that need to suppressed by specific subtypes of CeAGA analgesic neurons in all models, and such information will be critical for developing precise CeAGA-based therapies. In summary, this research is expected to identify and validate a novel central analgesic circuit whose power can be harnessed to treat chronic pain.

摘要 慢性疼痛是困扰三分之一美国人的主要健康问题。新的研究可以帮助 迫切需要开发新的止痛策略。我们的建议侧重于确定和 验证一个新的中枢镇痛回路这个项目是基于一个高度创新的假设， 全身麻醉（GA）的强镇痛作用部分是通过GA介导的激活 内源性镇痛回路在初步研究中，我们发现一个GABA能神经元的子集， 位于中央杏仁核（CeA）的核团被强烈激活并表达高水平的即时 GA下的早期基因Fos（以下称为CeAGA神经元）。令人兴奋的是，利用我们最近开发的 活动依赖的标签系统称为CANE（捕获激活的神经元包围），我们能够 捕获CeAGA神经元，并发现激活这些神经元可以产生深刻的疼痛抑制作用， 在急性疼痛模型和慢性口面神经性疼痛模型中的作用。 基于这些令人兴奋的初步结果，我们建议识别和验证CeAGA神经元的镇痛作用， 在不同实验室进行的多个小鼠疼痛模型中的功能（Wang和Ji，共同PI）。在目标1中， 系统地激活和沉默CeAGA镇痛神经元并测试这种双- 调节疼痛的感官辨别和情感方面的定向操纵 在未处理小鼠和几种急性和慢性疼痛模型的小鼠模型中进行交叉验证 两个实验室之间。在aim 2中，我们将使用最先进的体内成像技术， 假设CeAGA镇痛神经元的自发活动在各种不同的情况下严重减少， 慢性疼痛模型与初始条件相比，导致这些模型中的疼痛超敏反应（由于 抑制这种内源性镇痛回路）;作为补充，我们将使用切片电生理学 研究正常和慢性疼痛中CeAGA镇痛神经元的内在和诱发特性的变化 可以解释体内活性改变的条件。在目标3中，根据初步结果， 广泛的轴突投射CeAGA到许多脑区，我们将确定CeAGA的关键子集 在不同的慢性疼痛模型中的镇痛作用的投射途径。我们希望能找到 在所有模型中需要被CeAGA镇痛神经元的特定亚型抑制的共同途径， 这些信息对于开发精确的CeAGA疗法至关重要。总之，这项研究 有望识别和验证一种新型的中枢镇痛回路， 慢性疼痛