Amygdala and Pain-Associated Mood Disorders

描述(申请人提供)：慢性疼痛通常导致病理性情绪变化和相关的认知障碍。根本上需要开发更好的治疗方法来治疗疼痛和共病的情绪障碍。对于慢性疼痛引起情绪变化的机制的具体和详细的信息是治疗进展所必需的。杏仁中央核(CE)主要由抑制性GABA能神经元组成。它们共同表达几种神经肽，这些神经肽可能作为共同传递物，调节疼痛和情绪的各个方面。因此，CE抑制的GABA能神经元可能是疼痛和情绪之间的关键环节。我研究的长期目标是为治疗与慢性疼痛相关的情绪障碍的精神药物的药物开发建立新的战略。这项研究的目的是确定杏仁核中的GABA信号调节慢性疼痛期间出现的焦虑、抑郁和记忆障碍的机制，并确定CE GABA神经元的特定大脑靶点。我的中心假设是，慢性疼痛期间伤害性输入的增加导致特定CE-GABA能神经元亚群的过度活动，对情绪处理产生负面影响，并在易感个体中诱导抑郁情绪。拟议研究的基本原理是，对情绪障碍发生的新机制的描述将为开发基于高选择性(潜在的GABA能)的治疗情绪和疼痛的药物的新的药理策略提供机会。有三个具体的目的将用来证明我的假设：1)确定杏仁核抑制亚群对与疼痛相关的行为变化的发展的相对贡献；2)评估杏仁核GABA活性增加对疼痛期间学习和记忆的后遗症；以及3)评估疼痛解决后对疼痛相关行为的长期后果。我将使用一种药物遗传学方法，允许在体内对G蛋白偶联受体信号进行空间和时间控制，以实现前两个目标，我将使用一种新开发的技术来逆转神经病理损伤，以实现最后一个目标。两位合作者将提供他们的专业知识。实验室拥有这一项目所需的设备和设施。这一贡献将是重要的，因为它将有助于识别杏仁核中特定的、功能不同的神经元群，以及它们在持续疼痛引发的焦虑和抑郁情绪发展中的作用。这项拟议的研究具有创新性，因为它是专门为评估特定CE人群的贡献而设计的，根据他们的神经递质表达来定义，对疼痛产生的焦虑和抑郁情绪的贡献。

DESCRIPTION (provided by applicant): Chronic pain often leads to pathological mood changes and associated cognitive impairment. There is a fundamental need for development of better therapeutic approaches for both the pain and the comorbid mood disorders. Specific and detailed information about mechanisms causing mood changes in chronic pain is required for treatment advances. The central nucleus of the amygdala (CE) mainly consists of inhibitory GABAergic neurons. They coexpress several neuropeptides that may serve as co-transmitters and modulate aspects of pain and mood. Therefore, the CE inhibitory GABAergic neurons are likely to be a critical link between pain and mood. The long-term goal of my research is to establish new strategies for pharmaceutical development of psychotropic medications for treatment of mood disorders associated with chronic pain. The study objective in this proposal is to determine the mechanism by which GABA signaling in the amygdala modulates manifestations of anxiety, depression and memory impairment that develop during chronic pain, and to identify the specific brain targets of the CE GABA neurons. My central hypothesis is that the over-activity of specific CE GABAergic neuronal subpopulations, brought on by the increased nociceptive input during chronic pain, negatively affects emotional processing and induces depressive mood in susceptible individuals. The rationale for the proposed studies is that description of a new mechanism underlying development of mood disorders will provide opportunities for the development of new pharmacological strategies based on highly selective (potentially GABAergic) drugs, for both mood and pain. Three specific aims will be used to prove my hypothesis: 1) determine the relative contributions of amygdalar inhibitory subpopulations to the development of behavioral changes associated with pain; 2) assess the sequelae of increased amygdalar GABA activity on learning and memory during pain and 3) evaluate the long-term consequences of pain, after the pain is resolved, on pain associated behavior. I will use a pharmacological-genetic approach that allows spatial and temporal control of G-protein coupled receptor signaling in vivo to address the first two aims and I will use a newly developed technique for reversal of neuropathic injury to accomplish the last aim. Two collaborators will provide their expertise. The laboratory has the equipment and facilities required for this project. This contribution will be significant because it will aid the identifiction of specific, functionally distinct, neuronal groups in the amygdala and their role in the development of anxiety and depressed mood triggered by persistent pain. The proposed research is innovative because it has been designed specifically to evaluate the contribution of specific CE populations, as defined by their neurotransmitter expression, to pain generated anxiety and depressive mood.