Mu Opioid Mediated Stress Regulation in BPD

描述(申请人提供)：一个分布的区域网络，包括皮质(例如前额叶皮质、前扣带回皮质、岛叶皮质)和皮质下(例如杏仁核、丘脑、腹侧纹状体)，在情绪刺激的呈现或情绪状态的体验期间，它们的突触活动增加。其中一些区域的功能和结构变化也与情绪障碍(例如，重度抑郁症)的病理生理学有关。相比之下，有关神经递质系统的信息相对较少，这些神经递质系统参与调节人类的情绪和情绪状态，进而涉及到交界性人格障碍(BPD)。有研究表明，内源性阿片系统(EOS)可能与一些BPD症状有关，如应激相关的镇痛、分离行为和自我伤害活动。我们实验室最近的工作也表明，在经历负面情绪状态时，EOS参与了情绪调节，以及对应激源的反应。因此，EOS可能会将BPD的感觉相关症状与这种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的受体位置和适当的动力学模型，可以检查神经递质的释放，以响应实验的挑战。利用这些技术，我们已经证明了u阿片受体介导的阿片神经传递参与了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。本提案将这项工作扩展到BPD患者志愿者和年龄和性别匹配的健康对照组。此外，还介绍了慢性应激对这些反应的个体间差异的影响。将进行二次分析，以初步检查Met158val COMT基因型对这些个体间变异的贡献。然后将使用客观(例如，HPA轴测量)和主观测量(例如，疼痛等级、情感状态、情绪)来检查这些遗传型和内表型影响的心理生理学后果。这些研究的结果将为在系统水平上了解BPD对应激源的神经化学和行为反应，以及与这种疾病密切相关的回路和调节机制提供基础。这些信息对于理解BPD症状的生物学机制以及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是至关重要的。

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.