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）：惊恐障碍（PD）是一种严重的使人衰弱的焦虑障碍。尽管有广泛的研究，PD的神经生物学仍然知之甚少。PD与分离和依恋现象密切相关，分离焦虑儿童对二氧化碳（CO2）表现出显着的敏感性，这是成人PD最重要的生物标志之一，表明连接恐慌和依恋的共同神经生物学底物。在临床前模型中，内源性阿片系统对分离和附着的调节具有显著的特异性。阿片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，阿片系统是CO2敏感性的关键调节剂。因此，内源性阿片功能的缺失可能是PD神经生物学的组成部分。内源性阿片系统活性的有力评价是单次给予5剂纳洛酮（阿片受体拮抗剂），并测量下丘脑-垂体-肾上腺（HPA）轴反应。五剂量纳洛酮/HPA轴方法是与μ阿片受体活性相关的内源性阿片活性的有力标志物。该项目的中心目标是在足够的PD患者样本中，在SSRI治疗前（基线）和治疗后，采用严格和精确的5剂量纳洛酮/HPA轴方法，确定PD患者是否存在异常的内源性阿片系统活性。中心假设是，与正常人相比，PD患者基线时内源性阿片活性降低。该提案还将通过在SSRI治疗8周后重复5剂纳洛酮程序来确定SSRI治疗对PD中阿片功能的影响，以确定中枢阿片活性的正常化是否与PD的临床改善相关。