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.

抽象的 慢性疼痛是困扰三分之一美国人的主要健康问题，新研究可以帮助缓解疼痛。 我们迫切需要制定新的缓解疼痛策略。 该项目基于一个高度创新的假设，即验证一种新的中枢镇痛回路。 全身麻醉 (GA) 的强镇痛作用部分是通过 GA 介导的 在初步研究中，我们发现 GABA 能神经元的一个子集。 位于中央杏仁核 (CeA) 的区域被强烈激活并表达高水平的即时信号 令人兴奋的是，使用我们最近开发的 GA 下的早期基因 Fos（以下简称 CeAGA 神经元）。 称为 CANE（捕获激活神经元集合）的活动依赖性标记系统，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远的疼痛抑制作用 对急性疼痛模型和慢性口面部神经性疼痛模型的影响。 基于这些令人兴奋的初步结果，我们建议识别并验证 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，我们将。 系统地激活和沉默 CeAGA 镇痛神经元并测试这种双作用的后果 调节疼痛的感觉辨别和情绪情感方面的定向操作 在幼稚小鼠和几种急性和慢性疼痛模型小鼠模型中进行交叉验证 在目标 2 中，我们将使用最先进的体内成像技术来测试 假设 CeAGA 镇痛神经元的自发活动在各种情况下都严重减少 慢性疼痛模型与初始条件相比，导致这些模型中的疼痛过敏（由于 这种内源性镇痛回路的抑制）；并且补充，我们将使用切片电生理学 检查正常和慢性疼痛中 CeAGA 镇痛神经元的内在和诱发特性的变化 可以解释目标 3 中体内活性变化的条件，基于显示的初步结果。 CeAGA 广泛的轴突投射到许多大脑区域，我们将确定 CeAGA 的关键子集 我们期望确定它们在不同慢性疼痛模型中的镇痛作用的预测途径。 所有模型中需要被 CeAGA 镇痛神经元特定亚型抑制的常见通路， 这些信息对于开发基于 CeAGA 的精确疗法至关重要。 预计将识别并验证一种新型的中枢镇痛回路，其能量可用于治疗 慢性疼痛。

项目成果

General anesthetics activate a potent central pain-suppression circuit in the amygdala.

全身麻醉剂激活杏仁核中有效的中枢疼痛抑制回路。

• 发表时间: 2020
• 影响因子: 25
• 作者: Hua, Thuy;Chen, Bin;Lu, Dongye;Sakurai, Katsuyasu;Zhao, Shengli;Han, Bao;Kim, Jiwoo;Yin, Luping;Chen, Yong;Lu, Jinghao;Wang, Fan
• 通讯作者: Wang, Fan