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

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，严重 医疗、精神、社会和经济后果。鉴于致命性服药过量的日益普遍 和其他与阿片类药物滥用相关的负面健康后果，迫切需要新的和创新的治疗方法 需要的。褪黑素是一种荷尔蒙和神经递质，主要由松果体产生，它扮演着 在建立日常和季节节律方面的作用。外源性褪黑素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。它还减弱了对 吗啡诱导条件性位置偏爱，降低可卡因强化行为。拉梅尔登和 Agomelatine是褪黑素受体的有效激动剂，在结构上与褪黑素相关，并获得批准 供人类使用。 这个项目将评估临床上可用的褪黑素激动剂对阿片类药物的作用， 自我管理，以及睡眠-觉醒周期的中断。中断大鼠的光-暗循环 口服吗啡摄入量的增加与血浆褪黑激素浓度的降低有关。这 发现，结合观察吗啡诱导的条件位置偏爱减弱后 给予外源性褪黑素，表明褪黑素激动剂可能有助于治疗 防止人类使用阿片类药物。 最近，我们发现用5-HT2CR激动剂氯酪蛋白进行预处理 增加可卡因的积极主观影响，暗示这一亚型的拮抗剂有作用。 5-HT2CR的拮抗剂是阿莫拉汀，而不是雷美替酮。这一特性，以及褪黑素 激动剂活性，可能会降低阿片类药物的增强作用。安非他明的抗抑郁作用可能 对于有药物滥用障碍的患者也是有益的。 一项初步的开放标签研究表明，药物滥用障碍患者的渴求有所减少 用阿格莫拉汀治疗。为了启动对阿片使用障碍的潜在治疗方法的评估，该项目将 用大鼠模型评估褪黑素激动剂加或不加化合物修饰5-HT2CR的效果 阿片类药物强化的行为。 具体目标： 1.测量Ramelteon对睡眠、耐受依赖和吗啡自我给药的影响； 2.评价联合应用褪黑素激动剂和5-HT2CR拮抗剂的Agomelatine； 3.评估Ramelteon和5-HT2CR激动剂LorCaserin的联合作用。 方法将杂交的Wistar大鼠维持在反转的光-暗循环中，并给予食物和吗啡自我刺激。 管理会议在白天的黑暗中进行。大鼠将被允许建立阿片类药物 通过自我注射吗啡而成瘾。睡眠和清醒行为的持续时间和连续性将 每天把老鼠放回笼子里的时候无创性地记录下来。当吗啡被抽走的时候 在为期一周的消退期内，褪黑激素激动剂将通过全天候剂量或一次- 每天在黑暗开始前一小时注射(活动期)。对非强化反应的影响 将被记录在灭绝和复活期间。褪黑素激动剂治疗将继续作为大鼠 被允许重新获得吗啡的自我给药。 在其他动物中，接受固定的、非偶然剂量的吗啡和褪黑素激动剂，整个睡眠- 唤醒周期将被无创记录；随后将对阿片类药物耐受性进行评估， 强迫游泳时的退缩和静止。抗氧化剂和炎症介质将是 在脑组织中测量。

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.