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

• 批准号: 7805233
• 负责人: BENEDICT J KOLBER
• 金额: $ 4.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805233
• 关键词: Acute Pain; Affect; Amygdaloid structure; Anxiety; Area; Arthritis; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Chronic; Complex; Control Locus; Emotional; Extracellular Signal Regulated Kinases; 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

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）：慢性疼痛对超过30%的人群造成严重负担。虽然许多研究都集中在外周和脊髓控制疼痛，我感兴趣的是评估大脑局部疼痛调制。杏仁核是焦虑、恐惧和学习行为等情绪加工的重要部位，是控制疼痛的高级部位。杏仁中央核（CeA）通过脊髓-桥脑-杏仁核疼痛通路接受伤害性信息输入，并通过其他杏仁核接受多模态感觉信息。 最近，我们的小组已经确定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激活对于炎性疼痛模型中的行为敏化是必需的，并且足以在不存在外周炎症的情况下产生对机械刺激的超敏反应。然而，在CeA的ERK的上游激活剂和下游效应剂仍然未知。有趣的是，通过CeA中的I组代谢型谷氨酸受体（mGluRs）的信号传导作为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mGluRs与ERK偶联以影响行为敏化和神经元兴奋性。因此，我们假设CeA组I mGluRs介导ERK信号的增加，以改变炎症过程中的行为敏化，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信号转导在调节ERK激活和行为敏化中的作用。目的二是利用电生理技术研究mGluR和ERK对神经元兴奋性的影响。 公共卫生相关性：我们对大脑中疼痛调制的理解不足，部分原因是慢性疼痛治疗效果相对较差。本研究计划旨在通过研究杏仁核中调节疼痛的信号机制来研究杏仁核（一个参与疼痛情绪反应的大脑区域）在慢性疼痛中的作用。在这一领域的疼痛调节机制的鉴定将有助于确定新的治疗开发的治疗靶点。