Translating Melatonin- and Serotonin-2C Interactions into Improved Treatments for Pain and Opioid-Use Disorders

将褪黑素和血清素 2C 的相互作用转化为疼痛和阿片类药物使用障碍的改进治疗方法

• 批准号: 10292939
• 负责人: KENNETH W. GRASING
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292939
• 关键词: Agonist; Animal Model; Animals; Antidepressive Agents; Antioxidants; Anxiety; Attenuated; Behavior; Bolus Infusion; Brain; Clinical; Cocaine; Cues; Darkness; Dependence; Disease; Dose; Drug Addiction; Drug Kinetics; Economics; Evaluation; Extinction (Psychology); Food; General Population; Health; Heroin Abuse; Home; Hormones; Hour; Human; Inflammation; Inflammation Mediators; Injections; Intake; Interruption; Light; Measures; Medical; Melatonin; Melatonin Receptors; Mental Depression; Mental Health; Methods; Modeling; Mood Disorders; Morphine; Naloxone; Neurotransmitters; Opiate Addiction; Opioid; Oral; Outcome; Overdose; Oxidative Stress; Pain management; Patients; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Pineal gland; Plasma; Play; Prevalence; Property; Rattus; Relapse; Reporting; Rewards; Role; Safety; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Severities; Sleep; Sleep Wake Cycle; Sleep disturbances; Substance abuse problem; Swimming; Translating; Veterans; Veterans Health Administration; Wistar Rats; Withdrawal; addiction; antagonist; antidepressant effect; awake; brain tissue; circadian; cocaine self-administration; conditioned place preference; craving; health care service utilization; improved; innovation; military veteran; morphine administration; mortality; motivated behavior; novel; open label; opiate tolerance; opioid abuse; opioid use; opioid use disorder; opioid withdrawal; pain perception; pain relief; prevent; receptor; reinforced behavior; social

Background Abuse of opioids is an important problem for the Veterans Health Administration, with serious medical, psychiatric, social, and economic consequences. Given the increasing prevalence of fatal overdose and other negative health outcomes associated with opioid abuse, new and innovative treatments are urgently needed. Melatonin is a hormone and neurotransmitter produced primarily by the pineal gland, which plays a role in establishing daily and seasonal rhythms. Exogenous melatonin decreases both opioid tolerance and the severity of withdrawal, which may decrease opioid-reinforced behavior. It also attenuates the expression of morphine-induced conditioned place preference and decreases cocaine-reinforced behavior. Ramelteon and agomelatine are potent agonists at melatonin receptors that are structurally related to melatonin and approved for human use. Rationale This project will evaluate clinically available melatonin agonists for their effects on opioid actions, self-administration, and disruption of the sleep-wake cycle. Interruption of the light-dark cycle in rats that increases oral morphine intake is associated with a decreased plasma concentration of melatonin. This finding, combined with observations of diminished morphine-induced conditioned-place preference after administration of exogenous melatonin, indicate that melatonin agonists may be useful as treatments to prevent opioid use in humans. Recently, we found that pretreatment with the serotonin-2C receptor (5-HT2CR) agonist lorcaserin increases the positive subjective effects of cocaine, suggesting a role for antagonists of this subtype. Agomelatine but not ramelteon acts as an antagonist at the 5-HT2CR. This property, as well as melatonin agonist activity, may decrease the reinforcing effects of opioids. Antidepressant effects of agomelatine may also be beneficial in patients with substance abuse disorders. A preliminary open-label study noted decreased craving in patients with substance abuse disorders treated with agomelatine. To initiate evaluation as potential treatments for opioid-use disorder, this project will assess the effects of melatonin agonists with or without compounds that modify the 5-HT2CR using a rat model of opioid-reinforced behavior. Specific Aims: 1. Measure Effects of Ramelteon on Sleep, Tolerance-Dependence, and Morphine Self-Administration; 2. Evaluate Agomelatine, A Combined Melatonin Agonist and 5-HT2CR Antagonist; and 3. Assess Combined Effects of Ramelteon and Lorcaserin, a 5-HT2CR Agonist. Methods Outbred Wistar rats will be maintained on a reversed light-dark cycle, with food- and morphine- self- administration sessions conducted during darkness in the daytime. Rats will be allowed to establish opioid dependence by self-administration of morphine. The duration and continuity of sleep and awake behaviors will be recorded noninvasively each day when rats are returned to home cages. As morphine is withdrawn during a one-week extinction period, melatonin agonists will be delivered either by around-the-clock dosing or once- daily injection one hour prior to the onset of darkness (active periods). Effects on non-reinforced responding will be recorded during extinction and reinstatement. Melatonin agonist treatments will be continued as rats are allowed to reacquire self-administration of morphine. In other animals that receive fixed, noncontingent doses of morphine and melatonin agonists, the entire sleep- wake cycle will be recorded noninvasively; with subsequent evaluations for opioid tolerance, precipitated withdrawal, and immobility during forced swimming. Antioxidant- and inflammatory- mediators will be measured in brain tissue.

背景 阿片类药物滥用是退伍军人健康管理局的一个重要问题，具有严重的 医疗、精神、社会和经济后果。鉴于致命过量用药的发生率不断增加 以及与阿片类药物滥用相关的其他负面健康结果，迫切需要新的和创新的治疗方法 需要。褪黑激素是一种激素和神经递质，主要由松果体产生，松果体起着 在建立日常和季节节奏方面的作用。外源性褪黑激素会降低阿片类药物耐受性和 戒断的严重程度，这可能会减少阿片类药物强化的行为。它还减弱了表达 吗啡诱导的条件性位置偏好并减少可卡因强化的行为。雷美替胺和 阿戈美拉汀是褪黑激素受体的有效激动剂，其结构与褪黑激素相关，并已获得批准 供人类使用。 基本原理该项目将评估临床上可用的褪黑激素激动剂对阿片类药物作用的影响， 自我管理和睡眠-觉醒周期的破坏。大鼠明暗循环的中断 口服吗啡摄入量的增加与褪黑激素血浆浓度的降低有关。这 结合吗啡诱导的条件性位置偏好减弱的观察结果 给予外源性褪黑激素，表明褪黑激素激动剂可能可用于治疗 防止人类使用阿片类药物。 最近，我们发现用 5-羟色胺-2C 受体 (5-HT2CR) 激动剂氯卡色林进行预处理 增加可卡因的积极主观作用，表明该亚型拮抗剂的作用。 阿戈美拉汀而非雷美替胺充当 5-HT2CR 拮抗剂。这个属性，还有褪黑素 激动剂活性，可能会降低阿片类药物的增强作用。阿戈美拉汀的抗抑郁作用可能 对患有药物滥用疾病的患者也有益。 一项初步的开放标签研究表明，患有药物滥用疾病的患者的渴望有所下降 用阿戈美拉汀治疗。为了启动对阿片类药物使用障碍的潜在治疗方法的评估，该项目将 使用大鼠模型评估褪黑激素激动剂与或不与修饰 5-HT2CR 的化合物的作用 阿片类药物强化行为。 具体目标： 1. 测量雷美替胺对睡眠、耐受依赖性和吗啡自我给药的影响； 2. 评估阿戈美拉汀，一种联合褪黑激素激动剂和 5-HT2CR 拮抗剂；和 3. 评估 Ramelteon 和 Lorcaserin（一种 5-HT2CR 激动剂）的联合作用。 方法 近交系 Wistar 大鼠将维持在相反的光暗循环中，并用食物和吗啡自我调节。 行政会议在白天的黑暗中进行。老鼠将被允许建立阿片类药物 自行服用吗啡产生依赖性。睡眠和清醒行为的持续时间和连续性将 每天当大鼠返回笼子时进行无创记录。由于吗啡在服药期间被撤除 在一周的消退期中，褪黑激素激动剂将通过全天候给药或一次性给药 每天在黑暗开始前一小时（活跃期）注射。对非强化反应的影响 将在灭绝和恢复期间被记录。褪黑激素激动剂治疗将继续作为大鼠 允许重新获得吗啡的自我给药。 在接受固定、非偶然剂量的吗啡和褪黑激素激动剂的其他动物中，整个睡眠过程 唤醒周期将以无创方式记录；随后对阿片类药物耐受性进行评估， 强迫游泳时的退缩和不动。抗氧化剂和炎症介质将 在脑组织中测量。