Pain, Nociception, and the Amygdal

疼痛、伤害感受和杏仁核

• 批准号: 7318428
• 负责人: Volker Neugebauer
• 金额: $ 29.73万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318428
• 关键词: Abbreviations; Action Potentials; Address; Affect; Affective; Amygdaloid structure; Animals; Area; Arthritis; Arts; Behavior; Behavioral; Bicuculline; Birds; Brain; Carrageenan; Cell Nucleus; Cells; Cellular Membrane; Cerebrospinal Fluid; Chromosome Pairing; Cognitive; Cognitive deficits; Control Animal; Control Groups; Data; Decision Making; Disinhibition; Effectiveness of Interventions; Electric Stimulation; Electrophysiology (science); Emotional; Emotions; Experimental Arthritis; Figs - dietary; Food; Funding; GABA Antagonists; Gambling; Goals; Hindlimb; Human; Impaired cognition; Impairment; In Vitro; Indium; Injection of therapeutic agent; Intervention; Intra-Articular Injections; Iowa; KLK3 gene; Kaolin; Knee; Knee joint; Lateral; Literature; Localized; Measures; Medial; Mediating; Microdialysis; Modeling; NMDA receptor antagonist; Neurons; Nociception; Numbers; Outcome Measure; Pain; Pain management; Patients; Pattern; Persistent pain; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Placement; Prefrontal Cortex; Principal Investigator; Process; Rattus; Reflex action; Relative (related person); Research Personnel; Research Project Grants; Rewards; Risk; Risk Behaviors; Role; Saline; Slice; Source; Spinal; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Thinking; Time; Translational Research; Ultrasonics; United States National Institutes of Health; Withdrawal; Work; awake; base; behavior test; clinically relevant; cognitive function; extracellular; high risk behavior; improved; in vivo; indexing; innovation; interdisciplinary approach; neurobiological mechanism; neuromechanism; neuronal excitability; novel; 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）。前额叶皮层在认知功能（包括决策和避免基于情绪的风险选择）中的作用已得到充分证实。最近在患有认知缺陷的疼痛患者中发现前额皮质功能受损。 mPFC 的主要输入源是基底外侧杏仁核 (BLA)，它是情绪-情感杏仁核回路中的关键元件。我们之前的研究表明，在关节炎疼痛模型中，从 BLA 到杏仁核中央核 (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 相互作用在疼痛认知影响中的作用，我们将采用结合行为、系统以及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完善的疼痛模型，即高岭土/角叉菜胶诱发的膝关节关节炎。将测试以下具体假设： 1. 恢复 BLA 和 mPFC 的正常功能可改善与疼痛相关的决策缺陷。 2. BLA投射神经元的疼痛相关敏化抑制mPFC神经元。 3. 疼痛会导致 BLA 中的突触可塑性，并增加从 BLA 到 mPFC 神经元的抑制传递。具体目标是： 1. 确定恢复 BLA（用 APS（一种 NMDA 受体拮抗剂）失活）和 mPFC（用荷包牡丹碱（GABAA 受体拮抗剂）抑制）的正常功能是否可以改善新型行为中与疼痛相关的认知障碍以人类决策赌博任务为模型的测试。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决定。 2. 分析关节炎对 BLA 和 mPFC 神经元的影响，并确定抑制 BLA 敏化（使用 APS）或去抑制 mPFC（使用荷包牡丹碱）是否可以逆转麻醉大鼠体内疼痛相关的 mPFC 神经元抑制。 3. 使用来自关节炎和对照动物的脑切片的全细胞膜片钳记录，确定关节炎对体外 BLA 和 BLA-mPFC 突触的兴奋性和抑制性突触传递的影响。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。如果我们的假设正确，拟议的研究将首次证明杏仁核损害 mPFC 功能，导致与疼痛相关的决策缺陷。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。