Mu Opioid Mediated Stress Regulation in BPD

描述（由申请人提供）：一个分布的区域网络，包括皮质（如前额叶皮质、前扣带皮质、岛叶皮质）和皮质下（如杏仁核、丘脑、腹侧纹状体），在呈现情绪刺激或体验情绪状态时增加突触活动。其中一些区域的功能和结构变化也与情绪障碍（如重度抑郁症）的病理生理学有关。相比之下，关于人类情绪和情绪状态调节的神经递质系统，以及边缘型人格障碍（BPD）的相关信息相对较少。有研究表明，内源性阿片系统（EOS）可能与一些BPD症状（如应激相关的镇痛、解离行为和自残活动）具有生理相关性。我们实验室最近的工作也暗示了EOS在消极情绪状态体验中的情感调节，以及对压力源的反应。因此，EOS可能将BPD的感觉相关症状与该疾病中存在的情感调节异常联系起来。利用放射性示踪剂标记特定受体位点和适当的动力学模型，可以检查神经递质释放以响应实验挑战。利用这些技术，我们已经证明了多阿片受体介导的阿片神经传递参与应激和情感反应的调节，以及性别和遗传对这些现象的影响。目前的建议将这项工作扩展到BPD患者志愿者和年龄和性别匹配的健康对照。还介绍了慢性应激对这些反应的个体间变化的额外影响。将进行二次分析，初步检查met158val COMT基因型对这些个体间变异的贡献。这些基因型和内表型影响的心理生理后果，然后将使用客观（例如，HPA轴测量）和主观测量（例如，疼痛评分，情感状态，情绪）进行检查。在这些研究中获得的结果将为系统级理解BPD对压力源的神经化学和行为反应，以及与该疾病有关的回路和调节机制提供基础。这一信息对于理解BPD症状的生物学机制至关重要，并指导未来对这种常见但知之甚少的疾病的研究和治疗干预。

DESCRIPTION (provided by applicant): A distributed network of regions, both cortical (e.g., prefrontal cortex, anterior cingulate cortex, insular cortex) and subcortical (e.g., amygdala, thalamus, ventral striatum), increase their synaptic activity during the presentation of emotional stimuli or the experience of emotional states. Functional and structural changes in some of these regions have also been implicated in the pathophysiology of mood disorders (e.g., Major Depression). By comparison, relatively little information has been acquired on the neurotransmitter systems involved in the regulation of emotional and mood states in humans, and by extension, in Borderline Personality Disorder (BPD). There are suggestions that the endogenous opioid system (EOS) may have physiological relevance to some BPD symptoms such as stress-related analgesia, dissociative behavior, and self-injurious activity. Recent work from our laboratory has also implicated the EOS in affective regulation during the experience of negative emotional states, as well as in response to stressors. The EOS may therefore interface sensory-related symptoms of BPD with abnormalities in affective regulation present in this disorder. The utilization of radiotracers labeling specific receptor sites and appropriate kinetic models allows the examination of neurotransmitter release in response to experimental challenges. Employing these techniques, we have demonstrated the involvement of mu-opioid-receptor mediated opioid neurotransmission in the regulation of stress and affective responses, as well as sex and genetic influences on these phenomena. The present proposal extends this work to BPD patient volunteers and age- and sex-matched healthy controls. The additional influence of chronic stress on interindividual variations in these responses is also introduced. Secondary analyses will be performed to preliminarily examine the contribution of met158val COMT genotypes to these interindividual variations. The psychophysiological consequences of these genotypic and endophenotypic influences will then be examined using both objective (e.g., HPA axis measures) and subjective measures (e.g., ratings of pain, affective states, mood). The results obtained in these studies will provide a foundation for a systems-level understanding of neurochemical and behavioral responses to a stressor in BPD, and the circuits and regulatory mechanisms critically involved in this disorder. This information is critical for the understanding of the biological mechanisms underlying the symptomatology of BPD, and to guide future research and treatment interventions in this common but poorly understood illness.