Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 8369080
• 负责人: Volker Neugebauer
• 金额: $ 33.47万
• 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/8369080
• 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 Delivery Systems; Drug Interactions; 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. PUBLIC HEALTH RELEVANCE: The complex nature of pain with its emotional and cognitive aspects necessitates a comprehensive analysis of higher brain functions, which is thus an important but understudied area of pain research. The proposed studies will identify a novel pain mechanism that involves failure of cognitive brain systems to control an emotional brain center, resulting in the persistence of pain and its emotional-affective component. This project will not only advance our knowledge of brain pain mechanisms but also provide novel targets to rescue impaired cognitive pain control, thus improving strategies for pain management.

描述（由申请人提供）：疼痛的多维特征提出了治疗挑战，需要更好地理解调节其复杂的情绪情感和认知方面的高级大脑功能（NIH PA-10-006）。该项目将继续为这些高级大脑机制提供有价值的见解。杏仁核（大脑的情绪中心）的神经可塑性现在被认为是疼痛情绪情感维度的关键因素。疼痛时杏仁核功能障碍还会通过损害内侧前额叶皮层 (mPFC) 功能而导致认知缺陷。因此，控制杏仁核活动是疼痛管理中理想的治疗目标。在这里，我们提出了一个新概念，即认知缺陷和皮质输出受损导致疼痛及其情绪的持续存在 情感成分。基于我们之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 驱动的对过度杏仁核活动的抑制组成，杏仁核活动在疼痛时受损，但可以恢复以缓解疼痛。三个特定目标 (SA) 将确定恶性循环的突触和细胞机制以及行为后果，其中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) 输出神经元的皮质控制需要激活杏仁核闰细胞团 (ITC) 中的抑制性神经元。目标是确定可以恢复皮质对疼痛时杏仁核功能障碍的控制的药理学靶点。其中包括用于激活 mPFC 神经元的代谢型谷氨酸受体 mGluR5、用于释放 mPFC 神经元过度突触抑制的大麻素受体 CB1，以及用于选择性激活抑制 CeA 神经元的 ITC 细胞（前馈抑制）的新型神经肽 S (NPS)。行为实验 (SA1) 将检验以下假设：通过药理学恢复 mPFC-杏仁核控制将减轻疼痛并缩短其持续时间。将测量伤害行为、情绪情感和认知行为。体内电生理学 (SA2) 将检查疼痛时 mPFC-ITC-CeA 通路的功能障碍，以 mPFC 和 ITC 失活以及 CeA 过度活跃来衡量。药物救援策略将受到测试。 SA1和SA2将使用立体定位和全身药物应用。脑切片 (SA3) 的膜片钳研究将确定 mGluR5 和 CB1 对 mPFC 输出的突触和细胞调节以及 NPS 对 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标在恢复 mPFC-ITC-CeA 电路各个突触正常传输方面的有用性。这些概念上新颖的研究将确定皮质杏仁核控制缺陷是持续性疼痛的重要机制。他们将提供新的目标来恢复认知控制功能以缓解疼痛。对疼痛中高级脑功能和药物靶点的机制分析将增强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。 公共健康相关性：疼痛及其情绪和认知方面的复杂性需要对高级大脑功能进行全面分析，因此这是疼痛研究的一个重要但尚未充分研究的领域。拟议的研究将确定一种新的疼痛机制，该机制涉及认知大脑系统无法控制情绪大脑中心，导致疼痛及其情绪情感成分的持续存在。该项目不仅将增进我们对大脑疼痛机制的了解，还将提供新的目标来挽救认知疼痛控制受损，从而改进疼痛管理策略。