Mu Opioid Mediated Stress Regulation in BPD

描述（由申请人提供）：区域的分布式网络，包括皮质（例如，前额皮质、前扣带皮质、岛叶皮质）和皮质下（例如，杏仁核、丘脑、腹侧纹状体），在呈现情绪刺激或体验情绪状态期间增加它们的突触活动。这些区域中的一些区域的功能和结构变化也与情绪障碍的病理生理学有关（例如，抑郁症）。相比之下，关于人类情绪和情绪状态调节所涉及的神经递质系统的信息相对较少，并且延伸到边缘型人格障碍（BPD）。有证据表明，内源性阿片系统（EOS）可能与一些BPD症状（例如压力相关镇痛、分离行为和自伤活动）具有生理相关性。我们实验室最近的工作也暗示了EOS在负面情绪状态体验期间的情感调节以及对压力源的反应。EOS可能因此接口的感觉相关症状的BPD与情感调节异常，目前在这种疾病。利用放射性示踪剂标记特定的受体位点和适当的动力学模型，允许检查神经递质释放响应实验的挑战。采用这些技术，我们已经证明了μ阿片受体介导的阿片类神经传递参与调节压力和情感反应，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。慢性应激对这些反应的个体间差异的额外影响也被引入。将进行二次分析，以初步研究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将使用两个客观的（例如，HPA轴测量）和主观测量（例如，疼痛、情感状态、情绪的评级）。在这些研究中获得的结果将提供一个系统水平的理解的神经化学和行为反应的压力在BPD，电路和监管机制，关键参与这种疾病的基础。这些信息对于理解BPD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.