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: 10045505
• 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/10045505
• 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; Structure; Substance abuse problem; Swimming; Translating; Veterans; Veterans Health Administration; Wistar Rats; Withdrawal; addiction; 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面临的一个重要问题， 医疗、精神、社会和经济后果。鉴于吸毒过量致死的情况越来越普遍 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。 needed.褪黑激素是一种主要由松果体产生的激素和神经递质， 在建立日常和季节性节奏中的作用。外源性褪黑激素降低阿片类药物耐受性， 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 吗啡诱导的条件性位置偏爱和减少可卡因强化行为。Ramelteon和 阿戈美拉汀是褪黑激素受体的有效激动剂，其在结构上与褪黑激素相关，并被批准用于治疗糖尿病。 供人类使用。 基本原理本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-觉醒周期的中断。老鼠的光暗周期的中断， 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 这一发现，结合吗啡诱导的条件性位置偏好减弱的观察， 外源性褪黑激素的施用表明褪黑激素激动剂可用作治疗 防止阿片类药物在人类中的使用。 最近，我们发现5-羟色胺2C受体（5-HT 2CR）激动剂氯卡色林预处理 增加可卡因的积极主观效果，表明该亚型拮抗剂的作用。 阿戈美拉汀（而非雷美琼）可作为5-HT 2CR的拮抗剂。这种特性，以及褪黑激素 激动剂活性，可能会降低阿片类药物的强化作用。阿戈美拉汀的抗抑郁作用可能 也有益于物质滥用障碍患者。 一项初步的开放标签研究指出， 用阿戈美拉汀治疗为了开始评估阿片类药物使用障碍的潜在治疗方法，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-HT 2CR的化合物的作用 阿片类药物强化的行为 具体目标： 1.雷美琼对睡眠、耐受依赖和吗啡自我给药的影响 2.评价阿戈美拉汀，一种联合褪黑素激动剂和5-HT 2CR拮抗剂;和 3.评估Ramelteon和5-HT 2CR激动剂Lorcaserin的联合作用。 方法将远交Wistar大鼠维持在一个颠倒的光-暗周期中，用食物和吗啡自我维持。 在白天的黑暗中进行给药。将允许大鼠建立阿片样物质 依赖吗啡的自我管理。睡眠和清醒行为的持续时间和连续性将 每天将大鼠放回饲养笼时进行非侵入性记录。当吗啡被撤去时， 一周的消退期，褪黑激素激动剂将通过全天候给药或一次给药- 每天在黑暗开始前1小时注射（活动期）。对非强化反应的影响 将在灭绝和恢复期间记录。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管理。 在其他接受固定剂量的吗啡和褪黑激素激动剂的动物中，整个睡眠- 将无创记录清醒周期;随后评估阿片类药物耐受性， 在强迫游泳时退缩和不动。抗氧化剂和炎症介质将是 在脑组织中测量。