Cellular and molecular mechanisms undelying amygdala-dependent pain modulation

杏仁核依赖性疼痛调节的细胞和分子机制

基本信息

批准号：
8032461
负责人：
BENEDICT J KOLBER
金额：
$ 4.35万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2011-12-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8032461
关键词：
Acute Pain Affect Amygdaloid structure Anxiety Area Arthritis Behavior Behavioral Brain Brain region Cell Nucleus Cells Chronic Complex Control Locus Emotional Formalin Fright Future Human Hypersensitivity Inflammation Knowledge Lead Learning Mechanics Mediating Metabotropic Glutamate Receptors Mitogen-Activated Protein Kinases Modeling Molecular Mus Neurons Nociception Pain Pain management Pathway interactions Patients Peripheral Phorbol Phorbols Population Process Research Role Sensory Signal Transduction Site Spinal Cord Stimulus Techniques Training Treatment Efficacy base behavioral sensitization chronic pain design experience inflammatory pain inhibitor/antagonist interdisciplinary approach interest neuronal excitability new therapeutic target novel patch clamp public health relevance receptor coupling research study response therapy development tool

项目摘要

DESCRIPTION (provided by applicant): Chronic pain presents a serious burden to human patients afflicting over 30% of the population. Although much research has focused on the peripheral and spinal cord control of pain, I am Interested In evaluating brain-localized pain modulation. The amygdala, an important site for emotional processing of anxiety, fear and learning behaviors, is well situated to be a higher order locus for the control of pain. The central nucleus of the amygdala (CeA) receives nociceptive Inputs via the spino-ponto- amygdaloid pain pathway and polymodal sensory Information via other amygdalar nuclei. Recently, our group has identified a critical role for extracellular-signal regulated kinase (ERK) signaling in the CeA of mice. ERK activation in the CeA is both necessary for behavioral sensitization in a model of inflammatory pain and sufficient to produce hypersensitivity to mechanical stimuli in the absence of peripheral inflammation. However, the upstream activators and downstream effectors of ERK in the CeA remain unknown. Interestingly, signaling through group I metabotropic glutamate receptors (mGluRs) in the CeA serves as an important component in the behavioral and cellular response to arthritic pain. In the spinal cord, group I mGluRs couple to ERK to affect behavioral sensitization and neuronal excitability. Therefore, we hypothesize that CeA group I mGluRs mediate increases In ERK signaling to alter behavioral sensitization during inflammation and to modulate neuronal excitability in the amygdala. In our first specific aim, we will use pharmacological techniques to evaluate the role of group I mGluR signaling in modulating ERK activation and behavioral sensitization. In aim two, we will use electrophysiological techniques to evaluate the effect of mGluR and ERK on neuronal excitability. PUBLIC HEALTH RELEVANCE: Our poor understanding of pain modulation In the brain is partially responsible for the relatively poor efficacy of treatments for chronic pain. This research plan Is designed to study the role of the amygdala, a brain region Involved In emotional responses to pain, in chronic pain by focusing on the signaling mechanisms in the amygdala that regulate pain. Identification of the mechanisms of pain modulation in this area will aid in the identification of therapeutic targets for novel treatment development.

描述（由申请人提供）：慢性疼痛给人类患者带来了严重的负担，影响了超过 30% 的人口。尽管许多研究都集中在外周和脊髓对疼痛的控制上，但我对评估大脑局部疼痛调节很感兴趣。杏仁核是处理焦虑、恐惧和学习行为等情绪的重要场所，是控制疼痛的高级位点。杏仁核中央核 (CeA) 通过棘桥杏仁疼痛通路接收伤害性输入，并通过其他杏仁核接收多模式感觉信息。最近，我们的研究小组发现了细胞外信号调节激酶 (ERK) 信号在小鼠 CeA 中的关键作用。 CeA 中的 ERK 激活既是炎性疼痛模型中行为敏化所必需的，又足以在没有外周炎症的情况下产生对机械刺激的超敏反应。然而，CeA 中 ERK 的上游激活子和下游效应子仍然未知。有趣的是，通过 CeA 中的 I 类代谢型谷氨酸受体 (mGluR) 发出的信号是对关节炎疼痛的行为和细胞反应的重要组成部分。在脊髓中，I 组 mGluR 与 ERK 偶联，影响行为敏感性和神经元兴奋性。因此，我们假设 CeA I 组 mGluR 介导 ERK 信号传导增加，从而改变炎症期间的行为敏感性并调节杏仁核中的神经元兴奋性。在我们的第一个具体目标中，我们将使用药理学技术来评估 I 组 mGluR 信号传导在调节 ERK 激活和行为敏化中的作用。在目标二中，我们将使用电生理学技术来评估 mGluR 和 ERK 对神经元兴奋性的影响。公共卫生相关性：我们对大脑疼痛调节的了解不足是慢性疼痛治疗效果相对较差的部分原因。该研究计划旨在通过关注杏仁核中调节疼痛的信号机制来研究杏仁核（参与对疼痛的情绪反应的大脑区域）在慢性疼痛中的作用。确定该领域的疼痛调节机制将有助于确定新治疗开发的治疗靶点。