Role of lateral hypothalamus projections in opioid withdrawal-induced sleep deficits

下丘脑外侧投射在阿片类药物戒断引起的睡眠缺陷中的作用

• 批准号: 10516885
• 负责人: ELENA H CHARTOFF
• 金额: $ 25.65万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516885
• 关键词: Affect; Analgesics; Animal Model; Arousal; Brain; Brain region; Cessation of life; Chronic; Clinical Research; Data; Dependence; Devices; Dose; Drug Exposure; Electroencephalogram; Female; Foundations; Functional disorder; Future; G-Protein-Coupled Receptors; Goals; Human; Hypothalamic structure; Intervention Studies; Knowledge; Lateral; Lead; Light; Literature; Maps; Mediating; Mental disorders; Methods; Mission; Modeling; National Institute of Drug Abuse; Nature; Neurons; Neuropeptides; Opiate Addiction; Opioid; Oxycodone; Pathologic; Patients; Pattern; Persons; Pharmaceutical Preparations; Preventive; Process; Public Health; Publishing; Pump; REM Sleep; Rattus; Regulation; Relapse; Research; Resolution; Role; Saline; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Stages; Sleep disturbances; Sleeplessness; Staging; Structure of paraventricular nucleus of thalamus; Substance Use Disorder; Substance Withdrawal Syndrome; Techniques; Telemetry; Temperature; Testing; Therapeutic; Time; United States National Institutes of Health; Viral Vector; Wakefulness; Withdrawal; Withdrawal Symptom; Work; abuse liability; antagonist; awake; base; cost; craving; designer receptors exclusively activated by designer drugs; experience; experimental study; hypocretin; improved; insight; male; multimodality; negative affect; neurobiological mechanism; neurophysiology; non rapid eye movement; novel; opioid use; opioid use disorder; opioid withdrawal; overdose death; paraventricular nucleus; preclinical study; prescription opioid; prevent; rapid eye movement; receptor; relating to nervous system; signal processing; transmission process; vigilance

Project Summary. Prescription opioids such as oxycodone are highly effective analgesics and hence almost ubiquitously prescribed, resulting in high rates of abuse and opioid use disorder (OUD), which has resulted in an estimated 400,000 deaths in the US since 1999. The treatment course of OUD is primarily challenged by the opioid withdrawal syndrome: one of the most ubiquitous opioid withdrawal symptoms in humans is disrupted sleep—primarily a reduction in REM sleep and insomnia. Despite the debilitating effects of insomnia in OUD, there is little known on the impact of opioid withdrawal on sleep dynamics and the relevant role of sleep-related brain circuits. However, promising linkages have been shown between regions related to OUD and known arousal networks involved in sleep. In particular, opioid withdrawal stimulates lateral hypothalamic (LH) release of the neuropeptide orexin (ORX) into the paraventricular nucleus of the thalamus (PVT). Activation of the PVT, in turn, has been shown to promote wakefulness and negative affect, two hallmarks of opioid withdrawal. By probing LH ORX-mediated transmission within the PVT, we can therefore determine if these networks are necessary for the effect of opioid withdrawal on sleep. Additionally, current approaches to sleep electroencephalogram (EEG) analysis greatly limit the degree to which sleep dynamics can be described— discretizing the brain state during sleep by averaging over subjectively-identified sleep stages. By using objective, high-resolution EEG statistical signal processing and modeling approaches, we can better understand the effect of opioid use and withdrawal on neural oscillatory dynamics during sleep. Based on the literature and our own preliminary data showing oxycodone withdrawal-induced activation of the PVT and robust changes in sleep architecture and dynamics, we hypothesize that opioid withdrawal disrupts sleep via changes in the function of LHPVT ORX neurons. Specific Aim 1 will characterize the effect of oxycodone withdrawal on sleep architecture and sleep dynamics in male and female rats. We will characterize the time-varying effects of 10-d of withdrawal from chronic, escalating-dose oxycodone on sleep architecture and oscillatory dynamics using continuous recording of EEG, EMG, and temperature. Specific Aim 2 will determine if ORX LH neurons are necessary for oxycodone withdrawal-induced changes in sleep. We will use an intersectional viral vector approach with DREADDs to selectively activate or inhibit LHPVT neurons, quantifying the effect of on sleep architecture and dynamics. To test for a specific role of ORX, the ORX antagonist suvorexant will be administered with or without DREADD-mediated LHPVT modulation. If activation of LHPVT ORX projections mediates opioid-induced sleep disruptions, then inhibition of these projections will reduce, whereas activation will increase, oxycodone withdrawal-induced sleep deficits. Paired with a knowledge of EEG oscillatory mechanisms, these experiments will provide an enhanced understanding of the role LH and PVT, suggesting more specific mechanistic targets for future interventional studies.

项目摘要。处方阿片类药物（例如羟考酮）是高效的镇痛药，因此几乎 普遍处方，导致滥用和阿片类药物使用障碍（OUD），这导致了 自1999年以来，美国估计有40万人死亡。 阿片类药物戒断综合征：人类中最普遍的阿片类药物戒断症状之一被中断 睡眠 - 主要减少REM睡眠和失眠。尽管失眠在OUD中产生了令人衰弱的影响，但 关于阿片类药物戒断对睡眠动态的影响以及与睡眠有关的作用鲜为人知 脑电路。但是，与OUD和已知的地区之间显示了有希望的联系 涉及睡眠的唤醒网络。特别是，阿片类药物戒断刺激下丘脑（LH）释放 神经肽OREXIN（ORX）的脑腔（PVT）核核核心。激活PVT， 反过来，已证明可以促进清醒和负面影响，这是阿片类药物戒断的两个标志。经过 探测PVT中LH ORX介导的传输，因此我们可以确定这些网络是否为 阿片类药物戒断对睡眠的影响所必需的。此外，目前的睡眠方法 脑电图（EEG）分析极大地限制了可以描述睡眠动态的程度 - 通过平均主观识别的睡眠阶段平均，在睡眠过程中离散大脑状态。通过使用 客观的高分辨率脑电图统计信号处理和建模方法，我们可以更好地理解 阿片类药物使用和戒断对睡眠过程中神经振荡动力学的影响。基于文学和 我们自己的初步数据，显示了羟考酮戒断引起的PVT激活，并在 睡眠体系结构和动态，我们假设阿片类药物的戒断通过变化破坏了睡眠 LHPVTORX神经元的功能。特定的目标1将表征羟考酮戒断对睡眠的影响 雄性和雌性老鼠的建筑和睡眠动态。我们将表征10-D的随时间变化效果 使用睡眠结构上的慢性剂量羟考酮升级，并使用振荡动态 脑电图，EMG和温度的连续记录。特定的目标2将确定ORX LH神经元是否为 羟考酮戒断引起的睡眠变化所必需的。我们将使用交叉病毒载体 与Dreadds的接近，可以选择性激活或抑制LHPVT神经元，量化睡眠的影响 建筑和动态。为了测试ORX的特定作用，将施用ORX拮抗剂suvorexant 有或没有无dreadd介导的LHPVT调制。如果激活LHPVTORX预测媒体 卵毒素引起的睡眠破坏，然后抑制这些项目将减少，而激活将增加， 羟考酮戒断引起的睡眠不足。与脑电图振荡机制的了解相结合，这些 实验将增强对LH和PVT角色的理解，这表明更具体 未来介入研究的机械目标。