Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 6853617
• 负责人: Volker Neugebauer
• 金额: $ 34.92万
• 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/6853617
• 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）：关节炎疼痛与负面影响显著相关，如抑郁和焦虑。杏仁核在情绪和情感障碍中起着关键作用。在上一个研究期间，我们将杏仁核中央核（CeA）的侧囊部分描述为“伤害性杏仁核”。我们发现，在关节炎疼痛模型中，CeA中的多感受神经元产生伤害性可塑性，这是由谷氨酸受体的增强功能介导并依赖于谷氨酸受体的增强功能：伤害性传递通过mGluR 1亚型的突触前代谢型谷氨酸受体增强，神经元兴奋性通过突触后N-甲基-D-天冬氨酸（NMDA）的蛋白激酶A（PKA）依赖性磷酸化增加CeA中的受体。然而，PKA激活的机制尚不清楚。拟议的研究将分析两个主要的非阿片类神经肽，降钙素基因相关肽（CGRP）和促肾上腺皮质激素释放因子（CRF），在我们的高岭土/角叉菜胶关节炎疼痛模型的杏仁核中的作用。CGRP和CRF以特别高的水平存在于杏仁核中，并且它们的G蛋白偶联受体与PKA信号转导途径直接相关。我们将使用一种创新的和综合的药理学方法，结合行为测试和在体内和体外电生理学定义，在系统和细胞水平上，CGRP，CRF及其受体在伤害性处理和疼痛相关的可塑性在CeA的作用。本研究将测量清醒大鼠的自发探索行为、发声和超声发声，并采用在体麻醉大鼠的细胞外单细胞记录和离体大鼠脑片的全细胞膜片钳技术来验证以下假设：1. CGRP通过CGRP 1受体产生促伤害性作用，并且是关节炎疼痛中CeA中伤害性可塑性所需的。2. CRF通过CeA中的CRF 1受体具有抗伤害性作用，并通过CRF 2受体具有促伤害性作用。在关节炎疼痛中，CeA中的伤害性可塑性增强并需要促伤害性，但不抗伤害性。具体目标是：1。分析CGRP受体激动剂和拮抗剂对关节炎疼痛相关行为（a）、体内电生理（B）和体外电生理（c）的影响及其信号转导机制。2.确定CRF 1和CRF 2受体激动剂和拮抗剂对关节炎模型中疼痛行为（a）和电生理学（B）和体外（c）伤害感受可塑性测量的促伤害感受和抗伤害感受作用以及信号转导机制。这些研究将提供关于非阿片类神经肽在杏仁核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，与关节炎疼痛显著相关。创新和整合的行为和电生理在体内和体外的方法也将有助于有价值的洞察中枢非阿片类神经肽受体作为新的疼痛缓解靶点的潜在治疗价值。