Pain, Nociception and the Amygdala

疼痛、伤害感受和杏仁核

• 批准号: 8653991
• 负责人: Volker Neugebauer
• 金额: $ 13.73万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653991
• 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项治疗挑战，需要更好地理解更高的大脑功能，以调节其复杂的情绪影响和认知方面（NIH PA-10-006）。该项目将继续为这些更高的大脑机制提供宝贵的见解。情感大脑中心杏仁核中的神经可塑性现在被认为是疼痛情绪影响维度的关键因素。疼痛中的杏仁核功能障碍还通过损害内侧前额叶皮层（MPFC）功能引起认知缺陷。因此，控制杏仁核活性是疼痛管理中理想的治疗目标。在这里，我们推进了一个新颖的概念，即认知缺陷和皮质输出受损会导致疼痛的持久性及其情感 情感组成部分。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驱动的过度杏仁核活性组成，这会受到疼痛的损害，但可以恢复以缓解疼痛。三个具体目的（SAS）将确定恶性循环的突触和细胞机制以及行为后果，其中在关节炎大鼠疼痛模型中，MPFC异常失活导致MPFC驱动的杏仁核输出抑制。杏仁核（CEA）中央核中输出神经元的皮质控制需要激活杏仁核的插入细胞质量（ITC）中的抑制性神经元。目的是确定可以恢复疼痛中杏仁核功能障碍的皮质控制的药理学靶标。这些包括代谢型谷氨酸受体MGLUR5激活MPFC神经元，大麻素受体CB1以释放MPFC神经元的突触过多的突触抑制作用，以及新型的神经肽S（NPS）激活有选择性的ITC细胞，以抑制CEA神经元（喂养神经元）（喂养抑制）。行为实验（SA1）将检验以下假设：在药理学上恢复MPFC-Amygdala控制将减轻疼痛并缩短其持续时间。将测量单位性，情绪感染和认知行为。体内电生理学（SA2）将检查MPFC-ITC-CEA途径的功能障碍，以MPFC和ITC失效和CEA过度活跃性测量。将测试药理救援策略。 SA1和SA2将使用立体定位和全身药物应用。脑切片中的贴片钳研究（SA3）将确定MGLUR5和CB1对MPFC输出的突触和细胞调节的疼痛变化，以及NPS对CEA神经元的前馈抑制。贴片钳分析将阐明药理学靶标在MPFC-ITC-CEA电路的单个突触上恢复正常传播的有用性。这些概念上的新研究将确定皮质 - 杏仁核控制缺陷是持续疼痛的重要机制。他们将提供新的目标，以恢复认知控制功能以减轻疼痛。疼痛中较高的大脑功能和药物靶标的机械分析将促进基于证据的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。