Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 8487458
• 负责人: Volker Neugebauer
• 金额: $ 32.3万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487458
• 关键词: Acute; Affect; Affective; Agonist; Amygdaloid structure; Animals; Anxiety Disorders; Area; Arthritis; Basic Science; Behavior; Behavioral; Behavioral Assay; Behavioral Mechanisms; Brain; Brain Stem; CNR1 gene; Cannabinoids; Carrageenan; Cell Nucleus; Cells; Cognitive; Cognitive deficits; Complex; Control Groups; Corticotropin; Data; Dimensions; Disease; Disinhibition; Drug Interactions; Drug Targeting; Electrophysiology (science); Emotional; Emotions; Evidence Based Medicine; Failure; Functional disorder; GABA Receptor; Glutamates; Goals; Hyperactive behavior; Individual; Intercalated Cell; Interneurons; Kaolin; Knowledge; Lateral; Measures; Medial; Metabotropic Glutamate Receptors; Microdialysis; Modeling; Neurobiology; Neuronal Plasticity; Neurons; Neuropeptides; Nociception; Output; Pain; Pain Nature; Pain Research; Pain management; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Pharmacology; Phase; Play; Prefrontal Cortex; Process; Pyramidal Cells; Rattus; Research Project Grants; Saline; Slice; Staging; Stress; Synapses; System; Testing; Thalamic structure; Therapeutic; United States National Institutes of Health; Work; addiction; base; cognitive control; cognitive function; drug mechanism; extracellular; gamma-Aminobutyric Acid; improved; in vivo; inhibitory neuron; innovation; insight; interdisciplinary approach; knowledge base; neuropsychiatry; novel; patch clamp; receptor; research study; synaptic inhibition; transmission process

DESCRIPTION (provided by applicant): The multidimensional character of pain presents a therapeutic challenge that calls for better understanding of higher brain functions that regulate its complex emotional-affective and cognitive aspects (NIH PA-10-006). This project will continue to provide valuable insight into these higher brain mechanisms. Neuroplasticity in the amygdala, an emotional brain center, is now recognized as a key factor in the emotional-affective dimension of pain. Amygdala dysfunction in pain also causes cognitive deficits by impairing medial prefrontal cortex (mPFC) function. For that reason, control of amygdala activity is a desirable therapeutic goal in pain management. Here we advance the novel concept that cognitive deficits and impaired cortical output result in the persistence of pain and its emotional affective component. Based on our previous studies and preliminary data we propose the novel hypothesis that the cognitive control system for negative emotions consists of mPFC-driven inhibition of excessive amygdala activity, which is impaired in pain but can be restored for pain relief. Three Specific Aims (SAs) will determine synaptic and cellular mechanisms and behavioral consequences of a vicious cycle in which abnormal deactivation of the mPFC in a rat model of arthritis pain causes failure of mPFC-driven inhibition of amygdala output. Cortical control of output neurons in the central nucleus of the amygdala (CeA) requires activation of inhibitory neurons in the intercalated cell mass (ITC) of the amygdala. The goal is to identify pharmacological targets that can restore cortical control of amygdala dysfunction in pain. These include metabotropic glutamate receptor mGluR5 to activate mPFC neurons, cannabinoid receptor CB1 to release excessive synaptic inhibition of mPFC neurons, and novel neuropeptide S (NPS) to activate selectively ITC cells that inhibit CeA neurons (feedforward inhibition). Behavioral experiments (SA1) will test the hypothesis that restoring mPFC-amygdala control pharmacologically will decrease pain and shorten its duration. Nocifensive, emotional-affective and cognitive behaviors will be measured. Electrophysiology in vivo (SA2) will examine dysfunction of the mPFC-ITC-CeA pathway in pain, measured as mPFC and ITC deactivation and CeA hyperactivity. Pharmacological rescue strategies will be tested. SA1 and SA2 will use stereotaxic and systemic drug applications. Patch-clamp studies in brain slices (SA3) will determine pain-related changes of synaptic and cellular modulation of mPFC output by mGluR5 and CB1 and of feedforward inhibition of CeA neurons by NPS. Patch-clamp analysis will clarify the usefulness of pharmacological targets to restore normal transmission at individual synapses of the mPFC-ITC-CeA circuitry. These conceptually novel studies will identify cortico-amygdala control deficits as an important mechanism of persistent pain. They will provide novel targets to restore cognitive control functions for pain relief. The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide new and improved strategies for pain management.

描述（由申请人提供）：疼痛的多维特征提出了一个治疗挑战，需要更好地理解调节其复杂情感和认知方面的高级脑功能（NIH PA-10-006）。这个项目将继续提供有价值的洞察这些更高的大脑机制。杏仁核是大脑的一个情感中心，它的神经可塑性现在被认为是疼痛的情感维度的一个关键因素。疼痛中的杏仁核功能障碍也会通过损害内侧前额叶皮质（mPFC）功能而导致认知缺陷。因此，控制杏仁核活性是疼痛管理的理想治疗目标。在这里，我们提出了一个新的概念，即认知缺陷和受损的皮层输出导致疼痛的持续性及其情绪化。 情感成分基于我们以前的研究和初步数据，我们提出了一个新的假设，即负面情绪的认知控制系统由mPFC驱动的杏仁核过度活动的抑制，这是在疼痛中受损，但可以恢复疼痛缓解。三个特定目标（SA）将确定突触和细胞机制和恶性循环的行为后果，其中在关节炎疼痛大鼠模型中mPFC的异常失活导致mPFC驱动的杏仁核输出抑制失败。杏仁核中央核（CeA）中输出神经元的皮质控制需要杏仁核闰细胞团（ITC）中抑制性神经元的激活。目的是确定药理学目标，可以恢复杏仁核功能障碍的疼痛皮质控制。这些包括代谢型谷氨酸受体mGluR 5激活mPFC神经元，大麻素受体CB 1释放mPFC神经元的过度突触抑制，和新的神经肽S（NAPs）选择性激活ITC细胞，抑制CeA神经元（前馈抑制）。行为实验（SA 1）将测试恢复mPFC-杏仁核控制的疼痛将减少疼痛并缩短其持续时间的假设。将测量伤害性、情绪-情感和认知行为。体内电生理学（SA 2）将检查疼痛中mPFC-ITC-CeA通路的功能障碍，测量为mPFC和ITC失活和CeA活动过度。将测试药物补救策略。SA 1和SA 2将使用立体定位和全身药物应用。脑切片（SA 3）中的膜片钳研究将确定mGluR 5和CB 1对mPFC输出的突触和细胞调节以及CeA神经元的前馈抑制的疼痛相关变化。膜片钳分析将阐明药理学靶点在恢复mPFC-ITC-CeA回路的单个突触的正常传输方面的有用性。这些概念新颖的研究将确定皮质杏仁核控制缺陷作为持续性疼痛的重要机制。它们将提供新的靶点，以恢复疼痛缓解的认知控制功能。对疼痛中的高级脑功能和药物靶点的机制分析将促进循证医学所需的基础科学知识，并为疼痛管理提供新的和改进的策略。