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.

背景滥用阿片类药物是退伍军人卫生管理局的重要问题，严重 医学，精神病，社会和经济后果。考虑到致命过量的患病率增加 以及与阿片类药物滥用相关的其他负面健康结果，新的和创新的治疗方法是 需要。褪黑激素是一种激素和神经递质，主要由松果体产生，它发挥作用 在建立每日和季节性节奏中的作用。外源褪黑激素降低了阿片类药物的耐受性和 戒断的严重程度可能会降低阿片类药物增强的行为。它也削弱了 吗啡诱导的条件位置偏好，并降低可卡因增强的行为。 Ramelteon和 Agomelatine是褪黑激素受体的有效激动剂，在结构上与褪黑激素相关并批准 用于人类使用。 基本原理该项目将评估临床上可用的褪黑激动剂对阿片类药物作用的影响， 自我管理和睡眠效果周期的破坏。大鼠的光黑暗周期中断 口服吗啡摄入量的增加与血浆浓度降低有关。这 发现，结合了吗啡诱导的条件偏好后的观察结果 给药外源褪黑激素，表明褪黑激素激动剂可能作为治疗方法有用 防止在人类中使用阿片类药物。 最近，我们发现使用5-羟色胺-2C受体（5-HT2CR）激动剂Lorcaserin进行预处理 增加可卡因的积极主观作用，表明该亚型的拮抗剂的作用。 Agomelatine但不可用Ramelteon充当5-HT2CR的对手。该特性以及褪黑激素 激动剂活性可能会降低阿片类药物的增强作用。 agomelatine的抗抑郁作用可能 也对滥用药物疾病的患者有益。 一项初步的开放标签研究指出，药物滥用障碍患者的渴望减少了 用Agomelatine处理。为了作为对阿片类药物疾病的潜在治疗方法进行评估，该项目将 使用大鼠模型评估有或没有化合物，以有或没有化合物来修饰5-HT2CR的褪黑激动剂的作用 阿片类药物增强的行为。 具体目的： 1。衡量拉梅尔对睡眠，耐受性依赖性和吗啡自我管理的影响； 2。评估Agomelatine，一种联合褪黑激动剂和5-HT2CR拮抗剂；和 3。评估5-HT2CR激动剂Ramelteon和Lorcaserin的综合作用。 方法近交Wistar大鼠将保持在逆转的光黑暗周期，并具有食物和吗啡自我 白天在黑暗中进行的行政会议。将允许大鼠建立阿片类药物 吗啡的自我管理依赖性。睡眠和清醒行为的持续时间和连续性将 每天将老鼠返回家园时，每天都会记录下来。随着吗啡在期间撤回 为期一周的灭绝期，褪黑激激动剂将通过全天候给药或一次 - 黑暗发作前一小时（活跃时期）的每日注射。对非强化响应的影响 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 被允许重新征求吗啡的自我管理。 在接受固定的非剂量吗啡和褪黑激动剂的其他动物中，整个睡眠 唤醒周期将无创记录；随后评估阿片类药物的耐受性，沉淀 戒断和强迫游泳期间的戒烟。抗氧化剂和炎症介质将是 在脑组织中测量。