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: 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
• 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

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）：慢性疼痛给遭受30％以上人口的人类患者带来了严重负担。尽管大量研究集中在疼痛的周围和脊髓控制上，但我有兴趣评估脑部关闭疼痛调节。杏仁核是焦虑，恐惧和学习行为情绪处理的重要场所，位于疼痛控制疼痛的更高阶段。杏仁核（CEA）的中央核通过spino-ponto-杏仁核疼痛途径和多聚蛋白核的感觉信息接收伤害感受性输入。 最近，我们的小组确定了小鼠CEA中细胞信号调节激酶（ERK）信号传导的关键作用。在炎症性疼痛模型中，CEA中的ERK激活对于行为敏化都是必需的，并且在没有周围炎症的情况下足以产生对机械刺激的超敏反应。但是，CEA中ERK的上游激活剂和下游效应子仍然未知。有趣的是，通过I组通过CEA中的代谢型谷氨酸受体（MGLURS）发出信号是行为和细胞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夫妇与ERK相对，以影响行为敏感性和神经元兴奋性。因此，我们假设CEA组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。在我们的第一个特定目标中，我们将使用药理学技术来评估I组信号在调节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不良理解是部分原因是治疗慢性疼痛的功效相对较差。该研究计划旨在研究杏仁核（杏仁核）的作用，杏仁核是一种涉及对疼痛情绪反应的大脑区域，通过专注于调节疼痛的杏仁核的信号传导机制，从而在慢性疼痛中的情绪反应。鉴定该区域疼痛调节机制将有助于鉴定新的治疗发育的治疗靶标。