Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 7226892
• 负责人: Volker Neugebauer
• 金额: $ 0.4万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226892
• 关键词: NMDA receptors; amygdala; arthritis; biological signal transduction; brain electrical activity; calcitonin gene related peptide; central neural pathway /tract; chronic pain; corticotropin releasing factor; electrophysiology; emotions; glutamate receptor; inflammation; laboratory rat; neural information processing; neural plasticity; neural transmission; oscillography; pain; protein kinase A; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Arthritic pain is significantly associated with negative affect, such as depression and anxiety. The amygdala plays a key role in emotionality and affective disorders. In the previous grant period we delineated the laterocapsular part of the central nucleus of the amygdala (CeA) as the "nociceptive amygdala". We showed that in a model of arthritic pain multireceptive neurons in the CeA develop nociceptive plasticity, which is mediated by and dependent on the enhanced function of glutamate receptors: nociceptive transmission is enhanced through presynaptic metabotropic glutamate receptors of the mGluR1 subtype and neuronal excitability is increased through protein kinase A (PKA)-dependent phosphorylation of postsynaptic N-methyl-D-aspartate (NMDA) receptors in the CeA. The mechanism of PKA activation, however, is unknown. The proposed studies will analyze the role of two major non-opioid neuropeptides, calcitonin gene-related peptide (CGRP) and corticotropin releasing factor (CRF), in the amygdala in our kaolin/carrageenan arthritis pain model. CGRP and CRF are present at particularly high levels in the amygdala and their G-protein-coupled receptors are directly linked to the PKA signal transduction pathway. We will use an innovative and integrative pharmacological approach that combines behavioral tests and in vivo and in vitro electrophysiology to define, at the systems and cellular levels, the role of CGRP, CRF and their receptors in nociceptive processing and pain-related plasticity in the CeA. We will measure spontaneous exploratory behavior and audible and ultrasonic vocalizations in awake rats and use extracellular single-unit recordings in anesthetized rats in vivo and whole-cell patch-clamp in rat brain slices in vitro to test the hypotheses that: 1. CGRP produces pro-nociceptive effects through CGRP1 receptors and is required for nociceptive plasticity in the CeA in arthritis pain. 2. CRF has anti-nociceptive effects through CRF1 receptors and pro-nociceptive effects through CRF2 receptors in the CeA. The pro-nociceptive, but not anti-nociceptive, actions are enhanced and required for nociceptive plasticity in the CeA in arthritis pain. Specific aims are: 1. To analyze arthritis pain-related behavioral (a), electrophysiological in vivo (b) and in vitro (c) changes of CGRP receptor agonist and antagonist effects and their signal transduction mechanisms. 2. To define pro and anti-nociceptive effects and signal transduction mechanisms of CRF1 and CRF2 receptor agonists and antagonists on pain behavior (a) and electrophysiological in vivo (b) and in vitro (c) measures of nociceptive plasticity in the arthritis model. These studies will provide important new information on the role of non-opioid neuropeptides in pain mechanisms in the amygdala, a brain area that plays a key role in affective disorders, which are significantly associated with arthritic pain. The innovative and integrative behavioral and electrophysiological in vivo and in vitro approach will also contribute valuable insight into the potential therapeutic value of central non-opioid neuropeptide receptors as novel targets for pain relief.

描述（由申请人提供）：关节炎疼痛与抑郁症和焦虑等负面影响显着相关。杏仁核在情感和情感障碍中起关键作用。在上一个赠款期间，我们将杏仁核（CEA）中央核的后面部分描述为“伤害感受性杏仁核”。我们表明，在CEA中的关节炎疼痛多受感染性神经元的模型中，它会产生伤害性可塑性，这是由谷氨酸受体的功能增强并依赖于谷氨酸受体的增强功能：通过突触前抗抗抗甲虫的谷胱甘肽受体增强的MGLUR1亚型和神经素的特殊性（通过蛋白酶量）增强 - 蛋白酶的特殊性 - CEA中突触后N-甲基-D-天冬氨酸（NMDA）受体的磷酸化。但是，PKA激活的机制尚不清楚。拟议的研究将分析两种主要非阿片类神经肽，降钙素基因相关肽（CGRP）和皮质激素释放因子（CRF）在我们的高岭土/卡拉素关节炎疼痛模型中的杏仁核中的作用。 CGRP和CRF在杏仁核中特别高，其G蛋白偶联受体直接连接到PKA信号转导途径。我们将使用一种创新和综合的药理学方法，该方法结合了行为测试，体内和体外电生理学，以在系统和细胞水平，CGRP，CRF及其受体在伤害感受器处理中的作用以及CEA中与疼痛相关的可变性。 We will measure spontaneous exploratory behavior and audible and ultrasonic vocalizations in awake rats and use extracellular single-unit recordings in anesthetized rats in vivo and whole-cell patch-clamp in rat brain slices in vitro to test the hypotheses that: 1. CGRP produces pro-nociceptive effects through CGRP1 receptors and is required for nociceptive plasticity in the CeA in arthritis pain. 2. CRF通过CRF1受体具有抗伤害感受效应，并通过CEA中的CRF2受体促成伤害感受效应。促伤害性的，但没有抗伤害感受的作用，在关节炎疼痛的CEA中伤害性可塑性所必需。具体目的是：1。分析关节炎疼痛相关的行为（a），体内电生理学（b）和体外（c）CGRP受体激动剂和拮抗剂效应及其信号转导机制的变化。 2。定义CRF1和CRF2受体激动剂和拮抗剂的PRO和抗伤害感受效应以及体内疼痛行为（A）和电生理学的拮抗剂的信号转导机制（B）和体外（C）在关节炎模型中对伤害性可变性的测量。这些研究将提供有关非阿片类神经肽在杏仁核的疼痛机制中的作用的重要新信息，杏仁核是一个在情感障碍中起关键作用的大脑区域，与关节炎疼痛显着相关。体内和体外方法的创新和综合行为和电生理学还将为中枢性非阿联酋神经肽受体的潜在治疗价值提供宝贵的见解，作为缓解疼痛的新靶标。