Pain, Nociception, and the Amygdal

疼痛、伤害感受和杏仁核

• 批准号: 8016557
• 负责人: Volker Neugebauer
• 金额: $ 29.13万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016557
• 关键词: Abbreviations; Action Potentials; Address; Affect; Affective; Amygdaloid structure; Animals; Area; Arthritis; Behavior; Behavioral; Bicuculline; Brain; Carrageenan; Cell Nucleus; Cells; Cellular Membrane; Cerebrospinal Fluid; Cognitive; Cognitive deficits; Control Animal; Control Groups; Data; Decision Making; Disinhibition; Electric Stimulation; Electrophysiology (science); Emotional; Emotions; Experimental Arthritis; Food; Funding; GABA Antagonists; Gambling; Goals; Hindlimb; Human; Impaired cognition; Impairment; In Vitro; Indium; Injection of therapeutic agent; Intervention; Intra-Articular Injections; Iowa; Kaolin; Knee; Knee joint; Lateral; Literature; Measures; Medial; Mediating; Microdialysis; Modeling; NMDA receptor antagonist; Neurons; Nociception; Outcome Measure; Pain; Pain management; Patients; Pattern; Persistent pain; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Principal Investigator; Process; Rattus; Reflex action; Relative (related person); Research Project Grants; Rewards; Risk; Risk Behaviors; Role; Saline; Slice; Source; Spinal; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Translational Research; Ultrasonics; United States National Institutes of Health; Withdrawal; Work; awake; base; behavior test; clinically relevant; cognitive function; extracellular; high risk; high risk behavior; improved; in vivo; indexing; innovation; interdisciplinary approach; intervention effect; neurobiological mechanism; neuromechanism; neuronal excitability; novel; pain behavior; patch clamp; postsynaptic; preference; presynaptic; programs; receptor; research study; response; sensory stimulus; transmission process; vocalization

DESCRIPTION (provided by applicant): Cognitive impairment such as the inability to make advantageous decisions is one of the consequences of persistent pain but the underlying neural mechanisms are not known (NIH PA-06-544). The role of the prefrontal cortex in cognitive function, including decision-making and avoidance of emotion-based risky choices, is well established. Impaired prefrontal cortical function was recently shown in pain patients with cognitive deficits. A major source of input to the mPFC is the basolateral amygdala (BLA), a key element in the emotional-affective amygdala circuitry. Our previous studies showed enhanced synaptic transmission from the BLA to the central nucleus of the amygdala (CeA) in an arthritis pain model. We hypothesize that the BLA is an important structure underlying pain-related emotional-affective behavior (through projections to the CeA) and cognitive deficits (through connections with the mPFC). To determine the role of the BLA-mPFC interaction in cognitive effects of pain, we will use a multidisciplinary approach that combines behavior, systems and cellular electrophysiology and pharmacology. We will continue to use our well-established pain model, the kaolin/carrageenan-induced knee joint arthritis. The following specific hypotheses will be tested: 1. Restoring normal function in the BLA and mPFC improves pain-related decision-making deficits. 2. Pain-related sensitization of BLA projection neurons inhibits mPFC neurons. 3. Pain leads to synaptic plasticity in the BLA and increases inhibitory transmission from the BLA to mPFC neurons. The Specific Aims are: 1. Determine if restoring normal function in the BLA (deactivation with APS, an NMDA receptor antagonist) and in the mPFC (removing inhibition with bicuculline, a GABAA receptor antagonist) improves pain-related cognitive impairment in a novel behavioral test modeled after a decision-making gambling task in humans. Arthritic and control animals decide between disadvantageous high-risk and advantageous low-risk strategies based on food reward. 2. Analyze the effect of arthritis on BLA and mPFC neurons and determine if inhibiting BLA sensitization (with APS) or disinhibiting the mPFC (with bicuculline) reverse pain-related inhibition of mPFC neurons in anesthetized rats in vivo. 3. Determine the effect of arthritis on excitatory and inhibitory synaptic transmission in the BLA and at the BLA-mPFC synapse in vitro, using whole-cell patch-clamp recordings in brain slices from arthritic and control animals. This translational research project will determine the neurobiological mechanism by which pain produces clinically documented cognitive deficits. If our hypotheses are correct, the proposed studies will be the first to demonstrate that the amygdala impairs mPFC function resulting in pain-related decision-making deficits. The long-term goal of this project is the better understanding of higher brain functions involved in the different pain components to improve pain management strategies and decision making.

描述（由申请人提供）：认知障碍（例如无法做出有利决策）是持续疼痛的后果之一，但潜在的神经机制尚不清楚（NIH PA-06-544）。前额叶皮层在认知功能中的作用，包括决策和避免基于情绪的风险选择，已经建立了很好的确定。最近在患有认知缺陷的疼痛患者中显示了前额叶皮质功能受损。 MPFC的主要输入来源是基底外侧杏仁核（BLA），这是情绪感染杏仁核电路中的关键要素。我们先前的研究表明，在关节炎疼痛模型中，突触从BLA到杏仁核（CEA）的中央核的突触传播增强。我们假设BLA是与疼痛相关的情绪影响行为（通过对CEA的投射）和认知缺陷（通过与MPFC的连接）的重要结构。为了确定BLA-MPFC相互作用在疼痛的认知效应中的作用，我们将使用一种结合行为，系统和细胞电生理学和药理学的多学科方法。我们将继续使用良好的疼痛模型，高岭土/角叉菜素引起的膝关节炎。将测试以下特定假设：1。恢复BLA和MPFC中的正常功能可改善与疼痛相关的决策缺陷。 2。BLA投射神经元与疼痛相关的敏化抑制MPFC神经元。 3。疼痛导致BLA的突触可塑性，并增加从BLA到MPFC神经元的抑制传播。具体目的是：1。确定是否恢复BLA（用APS停用，NMDA受体拮抗剂）和MPFC中的正常功能（去除双核抑制，bicuculline，GABAA受体拮抗剂）会改善疼痛相关的认知障碍，以改善疼痛的认知障碍，这是在制定了决策范围的新型行为模型中的新型行为测试。关节炎和对照动物根据食物奖励决定不利于高风险的低风险策略。 2。分析关节炎对BLA和MPFC神经元的影响，并确定是否抑制BLA敏化（用APS）或抑制MPFC（用二瓜氨酸）反向疼痛与MPFC神经元的反向抑制在体外的大鼠中。 3。使用全细胞贴片钳在体外的兴奋性和抑制性突触传播对兴奋性和抑制性突触传播的影响，使用关节炎和对照动物的脑切片中的全细胞斑块钳记录。该转化研究项目将确定疼痛产生临床记录的认知缺陷的神经生物学机制。如果我们的假设是正确的，则提出的研究将是第一个证明杏仁核会损害MPFC功能，从而导致与疼痛相关的决策缺陷。该项目的长期目标是对不同疼痛组成部分中涉及的较高大脑功能的更高理解，以改善疼痛管理策略和决策。