Pain, Nociception and the Amygdala

描述(由申请人提供)：疼痛的多维特征是一个治疗挑战，需要更好地了解调节其复杂的情绪、情感和认知方面的高级大脑功能(NIH PA-10-006)。这个项目将继续为这些高级大脑机制提供有价值的见解。杏仁核是一个情绪大脑中心，它的神经可塑性现在被认为是疼痛情绪-情感维度的一个关键因素。疼痛中的杏仁核功能障碍也会通过损害内侧前额叶皮质(MPFC)功能而导致认知障碍。因此，控制杏仁核的活动是疼痛管理中一个理想的治疗目标。在这里，我们提出了一个新的概念，即认知缺陷和皮质输出受损会导致疼痛及其情绪的持续 情感成分。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，即对负面情绪的认知控制系统包括mPFC驱动的对杏仁核过度活动的抑制，杏仁核在疼痛中受损，但可以恢复以缓解疼痛。三个特定目标(SA)将确定一个恶性循环的突触和细胞机制和行为后果，在这个恶性循环中，在关节炎疼痛的大鼠模型中，mPFC的异常失活导致mPFC驱动的杏仁核输出抑制失败。杏仁中央核(CEA)的皮质控制输出神经元需要激活杏仁核(ITC)中的抑制性神经元。其目标是确定能够恢复疼痛时杏仁核功能障碍的皮质控制的药理靶点。其中包括激活mPFC神经元的代谢型谷氨酸受体mGluR5，释放mPFC神经元过度突触抑制的大麻素受体Cb1，以及选择性激活抑制CEA神经元的ITC细胞的新型神经肽S(NPS)(前馈抑制)。行为实验(SA1)将验证这样的假设，即从药物上恢复对mPFC-杏仁核的控制将减少疼痛并缩短疼痛持续时间。我们将测量学生的言语行为、情感行为和认知行为。体内电生理学(SA2)将检测疼痛中mPFC-ITC-CEA通路的功能障碍，测量为mPFC和ITC失活以及CEA过度活动。将对药物救援策略进行测试。SA1和SA2将使用立体定向和全身药物应用。脑片膜片钳研究(SA3)将确定mGluR5和CB1对mPFC输出的突触和细胞调制以及NPS对CEA神经元的前馈抑制的疼痛相关变化。膜片钳分析将阐明药物靶点在恢复mPFC-ITC-CEA回路个别突触的正常传递方面的作用。这些概念新颖的研究将确定皮质-杏仁核控制缺陷是持续性疼痛的重要机制。它们将为恢复缓解疼痛的认知控制功能提供新的靶点。对疼痛中高级大脑功能和药物靶点的机制分析将提高循证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。 与公共健康相关：疼痛及其情感和认知方面的复杂性质要求对高级大脑功能进行全面分析，因此这是疼痛研究的一个重要但未被充分研究的领域。这项拟议的研究将确定一种新的疼痛机制，涉及认知大脑系统无法控制情绪大脑中心，导致疼痛及其情绪-情感成分的持久性。该项目不仅将促进我们对脑疼痛机制的了解，还将为抢救认知疼痛控制受损的患者提供新的靶点，从而改进疼痛管理策略。

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. PUBLIC HEALTH RELEVANCE: The complex nature of pain with its emotional and cognitive aspects necessitates a comprehensive analysis of higher brain functions, which is thus an important but understudied area of pain research. The proposed studies will identify a novel pain mechanism that involves failure of cognitive brain systems to control an emotional brain center, resulting in the persistence of pain and its emotional-affective component. This project will not only advance our knowledge of brain pain mechanisms but also provide novel targets to rescue impaired cognitive pain control, thus improving strategies for pain management.