Identification and Validation of a Novel Central Analgesia Circuit
新型中枢镇痛回路的识别和验证
基本信息
- 批准号:10362236
- 负责人:
- 金额:$ 208.22万
- 依托单位:
- 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:2021-03-02 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph P Mathew其他文献
211 - Decreased Baroreflex Sensitivity After Surgery is Associated with Elevated Postoperative Pain: A Secondary Analysis
211 - 手术后压力反射敏感性降低与术后疼痛升高相关:一项二次分析
- DOI:
10.1016/j.jpain.2025.105009 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:4.000
- 作者:
Heberto Suarez-Roca;Negmeldeen Mamoun;Andrey V Bortsov;Joseph P Mathew - 通讯作者:
Joseph P Mathew
Joseph P Mathew的其他文献
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{{ truncateString('Joseph P Mathew', 18)}}的其他基金
Neurocognition and Greater Maintenance of Sinus Rhythm in AF (NOGGIN AF)
AF 中的神经认知和窦性心律的更好维持 (NOGGIN AF)
- 批准号:
10475214 - 财政年份:2021
- 资助金额:
$ 208.22万 - 项目类别:
Neurocognition and Greater Maintenance of Sinus Rhythm in AF (NOGGIN AF)
AF 中的神经认知和窦性心律的更好维持 (NOGGIN AF)
- 批准号:
10299458 - 财政年份:2021
- 资助金额:
$ 208.22万 - 项目类别:
Neurocognition and Greater Maintenance of Sinus Rhythm in AF (NOGGIN AF)
AF 中的神经认知和窦性心律的更好维持 (NOGGIN AF)
- 批准号:
10632044 - 财政年份:2021
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Resolution of Neuroinflammation and Persistent Pain by Complementary Approaches
通过补充方法解决神经炎症和持续性疼痛
- 批准号:
9703529 - 财政年份:2020
- 资助金额:
$ 208.22万 - 项目类别:
Cortical Beta-amyloid Levels and Neurocognitive Performance After Cardiac Surgery
心脏手术后皮质 β-淀粉样蛋白水平和神经认知功能
- 批准号:
8095975 - 财政年份:2011
- 资助金额:
$ 208.22万 - 项目类别:
Cortical Beta-amyloid Levels and Neurocognitive Performance After Cardiac Surgery
心脏手术后皮质 β-淀粉样蛋白水平和神经认知功能
- 批准号:
8306387 - 财政年份:2011
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$ 208.22万 - 项目类别:
Lidocaine for Neuroprotection During Cardiac Surgery
利多卡因在心脏手术期间的神经保护作用
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8475499 - 财政年份:2009
- 资助金额:
$ 208.22万 - 项目类别:
Lidocaine for Neuroprotection During Cardiac Surgery
利多卡因在心脏手术期间的神经保护作用
- 批准号:
7698221 - 财政年份:2009
- 资助金额:
$ 208.22万 - 项目类别:
Lidocaine for Neuroprotection During Cardiac Surgery
利多卡因在心脏手术期间的神经保护作用
- 批准号:
8075116 - 财政年份:2009
- 资助金额:
$ 208.22万 - 项目类别:
Lidocaine for Neuroprotection During Cardiac Surgery
利多卡因在心脏手术期间的神经保护作用
- 批准号:
7915376 - 财政年份:2009
- 资助金额:
$ 208.22万 - 项目类别:
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