Amygdala and Pain-Associated Mood Disorders

描述（由申请人提供）：慢性疼痛通常会导致病理性情绪变化和相关的认知障碍。对于疼痛和共病的情绪障碍，有一个更好的治疗方法的发展是一个根本的需要。关于慢性疼痛中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递质并调节疼痛和情绪。因此，CE抑制性GABA能神经元可能是疼痛和情绪之间的重要联系。我的研究的长期目标是为治疗慢性疼痛相关情绪障碍的精神药物的药物开发建立新的策略。本研究的目的是确定杏仁核中GABA信号传导调节慢性疼痛过程中出现的焦虑、抑郁和记忆障碍的机制，并确定CE GABA神经元的特定脑靶点。我的中心假设是，在慢性疼痛过程中增加的伤害性输入引起特定CE GABA能神经元亚群的过度活动，对易感个体的情绪处理产生负面影响，并诱导抑郁情绪。拟定研究的基本原理是，描述情绪障碍发展的新机制将为开发基于高选择性（潜在GABA能）药物的新药理学策略提供机会，用于情绪和疼痛。 三个具体的目标将被用来证明我的假设：1）确定杏仁核抑制亚群的相对贡献的发展与疼痛相关的行为变化; 2）评估后遗症增加杏仁核GABA活动的学习和记忆过程中的疼痛和3）评估疼痛的长期后果，疼痛后，疼痛相关的行为。我将使用一种药理学遗传学方法，允许在体内空间和时间控制G蛋白偶联受体信号传导，以解决前两个目标，我将使用一种新开发的逆转神经性损伤的技术来实现最后一个目标。两名合作者将提供他们的专业知识。实验室具备本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特定的，功能不同的，杏仁核中的神经元群及其在持续疼痛引发的焦虑和抑郁情绪的发展中的作用。拟议的研究是创新的，因为它是专门设计来评估特定CE人群的贡献，如他们的神经递质表达所定义的，疼痛产生的焦虑和抑郁情绪。

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.