Endogenous Opioid System in Panic Disorder: 5-Dose Naloxone Procedure and SSRI Tx

恐慌症中的内源性阿片类药物系统：5 剂量纳洛酮手术和 SSRI Tx

• 批准号: 8685334
• 负责人: SMIT S SINHA
• 金额: $ 10.8万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685334
• 关键词: Adult; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Biological; Biological Markers; Brain; Carbon Dioxide; Child; Clinical; Complex; Corticotropin; Development; Distress; Dose; Early Diagnosis; Evaluation; Functional disorder; Goals; Hydrocortisone; Individual; Light; Link; Measurement; Methodology; Mole the mammal; Moods; Naloxone; Neurobiology; Neuropeptides; Neurotransmitters; Opioid; Opioid Receptor; Panic; Panic Disorder; Patients; Physiological; Play; Pre-Clinical Model; Procedures; Regulation; Research; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Sertraline; Specificity; Stress; Substance abuse problem; Surrogate Markers; System; Therapeutic Agents; chronic pain; cost effective; endogenous opioids; hypothalamic-pituitary-adrenal axis; innovation; mu opioid receptors; neurobiological mechanism; new therapeutic target; novel; novel marker; novel therapeutics; public health relevance; response; treatment response

DESCRIPTION (provided by applicant): Panic disorder (PD) is a severe and debilitating anxiety disorder. Despite extensive research, the neurobiology of PD remains poorly understood. That PD is intimately linked to the phenomena of separation and attachment, and that separation anxious children display marked sensitivity to carbon dioxide (CO2), one of the most important biological markers of adult PD, suggests a common neurobiological substrate linking panic and attachment. The endogenous opioid system has remarkable specificity for the regulation of separation and attachment in preclinical models. The opioid system also modulates key neurotransmitter systems implicated in diverse anxiety states. Importantly, the opioid system is a critical regulator of CO2 sensitivity. Abnormalities in endogenous opioid function may therefore be integral to the neurobiology of PD. A powerful evaluation of endogenous opioid system activity is a single session administration of five doses of naloxone, an opioid receptor antagonist, and measurement of the hypothalamic-pituitary-adrenal (HPA) axis response. The five-dose naloxone/HPA axis methodology is a powerful marker of endogenous opioid activity that correlates with mu-opioid receptor activity. The central goal of this project is to determine if there is abnormal endogenous opioid system activity in PD with a rigorous and precise five-dose naloxone/HPA axis methodology in an adequate sample of PD patients, both before (baseline) and after SSRI treatment. The central hypothesis is that there will be decreased endogenous opioid activity at baseline in PD patients compared to normals. This proposal will also determine the effect of SSRI treatment on opioid function in PD by repeating the five-dose naloxone procedure after 8 weeks of SSRI treatment to determine if normalization of central opioid activity is associated with clinical improvement in PD.

描述（由申请人提供）：恐慌症（PD）是一种严重而令人衰弱的焦虑症。尽管进行了广泛的研究，但PD的神经生物学仍然知之甚少。该PD与分离和依恋的现象密切相关，分离焦虑的孩子表现出对二氧化碳（CO2）的明显敏感性（CO2），这是成人PD的最重要的生物学标记之一，这表明一种常见的神经生物学底物与恐慌和依恋联系。内源性阿片类药物系统对于临床前模型中的分离和附着的调节具有显着的特异性。阿片类药物系统还调节与各种焦虑状态有关的关键神经递质系统。重要的是，阿片类药物系统是CO2敏感性的关键调节剂。因此，内源性阿片类药物功能的异常可能是PD神经生物学不可或缺的。对内源性阿片类药物系统活性的有力评估是单次施用五剂纳洛酮，一种阿片受体拮抗剂，以及下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴反应的测量。五剂纳洛酮/HPA轴方法是内源性阿片类药物活性的强大标记，与MU-阿片类受体活性相关。该项目的核心目的是确定PD中的内源性阿片类药物系统活性是否存在严格而精确的五剂量纳洛酮/HPA轴方法，在适当的PD患者样本中，无论是在PD患者还是在SSRI治疗之前和SSRI治疗之后。中心假设是，与正常患者相比，PD患者的内源性阿片类药物活性将降低。该建议还将通过在SSRI治疗8周后重复五剂纳洛酮程序来确定SSRI治疗对PD中阿片类药物功能的影响，以确定中央阿片类药物活性的归一化是否与PD的临床改善有关。