Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 7193388
• 负责人: Volker Neugebauer
• 金额: $ 33.11万
• 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 2008-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193388
• 关键词: Pain; Nociception; Amygdala

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）：关节炎疼痛与抑郁和焦虑等负面情绪显着相关。杏仁核在情绪和情感障碍中起着关键作用。在之前的资助期间，我们将杏仁核中央核（CeA）的后囊部分描述为“伤害性杏仁核”。我们发现，在关节炎疼痛模型中，CeA 中的多感受性神经元会产生伤害性可塑性，这种可塑性是由谷氨酸受体的功能增强介导并依赖于谷氨酸受体的增强功能：通过 mGluR1 亚型的突触前代谢型谷氨酸受体增强伤害性传递，并且神经元兴奋性增加通过突触后 N-甲基-D-天冬氨酸的蛋白激酶 A (PKA) 依赖性磷酸化CeA 中的 (NMDA) 受体。然而，PKA 激活的机制尚不清楚。拟议的研究将分析两种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中杏仁核中的作用。 CGRP 和 CRF 在杏仁核中的含量特别高，它们的 G 蛋白偶联受体与 PKA 信号转导途径直接相关。我们将使用创新的综合药理学方法，结合行为测试和体内和体外电生理学，在系统和细胞水平上定义 CGRP、CRF 及其受体在 CeA 伤害性加工和疼痛相关可塑性中的作用。我们将测量清醒大鼠的自发探索行为以及可听和超声发声，并使用体内麻醉大鼠的细胞外单单元记录和体外大鼠脑切片的全细胞膜片钳来测试以下假设： 1. CGRP 产生 pro -通过 CGRP1 受体产生伤害感受作用，并且是关节炎疼痛中 CeA 伤害感受可塑性所必需的。 2. CRF通过CeA中的CRF1受体具有抗伤害感受作用，并通过CeA中的CRF2受体具有促伤害感受作用。在关节炎疼痛中，CeA 的促伤害感受作用而非抗伤害感受作用得到增强，并且是其伤害感受可塑性所必需的。具体目的是： 1.分析关节炎疼痛相关行为(a)、体内(b)和体外(c)CGRP受体激动剂和拮抗剂作用的电生理变化及其信号转导机制。 2. 确定 CRF1 和 CRF2 受体激动剂和拮抗剂对关节炎模型中疼痛行为 (a) 的促进和抗伤害作用以及信号转导机制，以及体内 (b) 和体外 (c) 伤害感受可塑性的体内电生理学测量。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，杏仁核是在情感障碍中发挥关键作用的大脑区域，而情感障碍与关节炎疼痛显着相关。创新和综合的行为和电生理学体内和体外方法也将为中枢非阿片类神经肽受体作为缓解疼痛的新靶点的潜在治疗价值提供有价值的见解。