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，如无法做出有利的决定是持续性疼痛的后果之一，但潜在的神经机制尚不清楚(NIH PA-06-544)。前额叶皮质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，已经得到了很好的证实。最近在有认知障碍的疼痛患者中表现出前额叶皮质功能受损。杏仁基底外侧核(BLA)是mPFC的一个主要输入来源，它是杏仁核情绪-情感回路中的一个关键元素。我们以前的研究表明，在关节炎疼痛模型中，从BLA到杏仁中央核(CEA)的突触传递增强。我们假设BLA是疼痛相关情绪-情感行为(通过向CEA的投射)和认知缺陷(通过与mPFC的联系)的重要结构。为了确定BLA-mPFC相互作用在疼痛认知效应中的作用，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。我们将继续使用我们已建立的疼痛模型，即高岭土/卡拉胶诱导的膝关节关节炎。将检验以下具体假设：1.恢复BLA和mPFC的正常功能可以改善与疼痛相关的决策缺陷。2.痛敏化BLA投射神经元抑制mPFC神经元。3.疼痛导致BLA的突触可塑性，增加了BLA向mPFC神经元的抑制性传递。具体目标是：1.在一项模仿人类决策赌博任务的新型行为测试中，确定恢复BLA(用NMDA受体拮抗剂APS去激活)和mPFC(用GABAA受体拮抗剂荷包牡丹碱解除抑制)中的正常功能是否能改善与疼痛相关的认知障碍。关节炎和对照动物根据食物奖励在不利的高风险和有利的低风险策略之间做出选择。2.分析关节炎对麻醉大鼠在体脑BLA和mPFC神经元的影响，确定APS抑制BLA敏化或荷包牡丹碱拮抗mPFC是否能逆转痛相关的mPFC神经元抑制。3.采用全细胞膜片钳记录技术，在体外研究关节炎对BLA和BLA-mPFC突触兴奋性和抑制性突触传递的影响。这项转化性研究项目将确定疼痛导致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，拟议的研究将是第一个证明杏仁核损害mPFC功能导致疼痛相关决策缺陷的研究。该项目的长期目标是更好地了解不同疼痛成分所涉及的高级大脑功能，以改进疼痛管理策略和决策。