Pain, Nociception, and the Amygdal

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。前额皮质功能受损最近在认知缺陷的疼痛患者中得到证实。mPFC的主要输入来源是基底外侧杏仁核（BLA），它是情绪-情感杏仁核回路的关键元素。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是与疼痛相关的情绪-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效应中的作用，我们将采用多学科方法，结合行为、系统、细胞电生理学和药理学。我们将继续使用我们完善的疼痛模型，高岭土/卡拉胶诱导的膝关节关节炎。以下具体假设将被检验：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. BLA投射神经元的疼痛相关敏化抑制mPFC神经元。3. 疼痛导致BLA的突触可塑性，并增加BLA到mPFC神经元的抑制性传递。具体目标是：1。在一项模拟人类决策赌博任务的新型行为测试中，确定恢复BLA(使用APS（一种NMDA受体拮抗剂）和mPFC(使用双管碱（一种GABAA受体拮抗剂）的正常功能是否能改善与疼痛相关的认知障碍。关节炎动物和对照组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BLA和mPFC神经元的影响，并确定抑制BLA致敏（APS）或去抑制mPFC（双库兰）是否能在体内逆转麻醉大鼠mPFC神经元的疼痛相关抑制。3. 使用全细胞膜片钳记录关节炎动物和对照动物的脑切片，确定关节炎对体外BLA和BLA- mpfc突触兴奋性和抑制性突触传递的影响。这个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，那么这些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涉及不同疼痛成分的高级大脑功能，以改善疼痛管理策略和决策。

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.