Medications for opioid use disorder differentially modulate intrinsically photosensitive retinal ganglion cell function, sleep, and circadian rhythms: implications for treatment

项目摘要 美国每年约有10万人死于阿片类药物过量或阿片类药物使用障碍的并发症 （OUD）。三种用于OUD（MOUD）的药物是FDA批准的，并经常用于治疗OUD：美沙酮， 丁丙诺啡和缓释纳洛酮（XR-NTX）。然而，使用阿片类药物的人，包括那些 规定的MOUD，报告睡眠中断。除了大脑的睡眠中心，μ阿片受体 MORs也在视网膜（包括人视网膜）中表达，特别是在神经节细胞中表达。 对于非成像光感受包括睡眠-觉醒行为的昼夜节律调节至关重要。 临床前研究表明，这些内在光敏视网膜神经节细胞上MORs的激活 （ipRGC）减少对光的电生理反应，影响关键的ipRGC功能，例如 睡眠-觉醒行为和昼夜节律对光的同步化（光诱导），光诱导 褪黑激素抑制和光照后瞳孔反射（PIPR）。这些结果表明， 通过阿片样物质使用和/或MOUD激活ipRGC中的MOR可能损害下游ipRGC功能。这 一项多学科的研究将检验一个新的总体假设，即睡眠/觉醒的持续改变， 接受治疗的OUD患者的行为由受损的ipRGC功能介导， 该途径可以预测恢复和复发。三个目标将在200名参与者的样本中进行测试，其中150名 将从事MOUD治疗的人（例如，美沙酮丁丙诺啡和XR-NTX各50人 其中50人将是使用非阿片样物质的对照参与者。目标1将检验以下假设： MOUD不同地影响ipRGC响应的功能。目标2将检查MOUD是否差异化 影响白天嗜睡、日常睡眠-觉醒行为、睡眠结构和睡眠呼吸障碍。 最后，目标3将确定ipRGC功能是否预测1-、3-和6-时MOUD组中的阿片样物质复发。 月随访。与使用非阿片类药物的对照组或接受阿片类药物拮抗剂（XR-NTX）的人相比， 我们预测接受激动剂（美沙酮）或部分激动剂（丁丙诺啡）MOUD的参与者 将具有最多的ipRGC干扰，如通过减少的PIPR、减弱的光诱导的褪黑激素 抑制、降低的昼夜节律幅度、增加的睡眠潜伏期和增加的睡眠碎片。 重要的是，我们假设受损的ipRGC功能将预测更差的治疗结果，如 6个月随访时阿片类药物使用情况。最后，一个探索性的目标将检查MOUD组是否显示 阿片类药物渴求/戒断症状与10天内睡眠-觉醒行为之间的不同关系 评估参与者在正常环境中的日常生活。这项研究的结果将是高度 重要的是，它将支持使用瞳孔对光的反应和ipRGC的其他指标 作为新的生物标志物来预测对MOUD的反应和结果。

PROJECT SUMMARY About 100,000 people die annually in the U.S. because of opioid overdose or complications of opioid use disorder (OUD). Three medications for OUD (MOUD) are FDA-approved and regularly used to treat OUD: methadone, buprenorphine, and extended-release naltrexone (XR-NTX). However, persons who use opioids, including those prescribed MOUDs, report sleep disruption. In addition to the sleep centers of the brain, mu opioid receptors (MORs) are also expressed in the retina (including the human retina), specifically in ganglion cells that are critically important for non-image forming photoreception including circadian regulation of sleep-wake behavior. Pre-clinical studies show that activation of MORs on these intrinsically photosensitive retinal ganglion cells (ipRGCs) reduces the electrophysiological response to light, impacting critical ipRGC functions such as synchronization of sleep-wake behavior and circadian rhythms to light (photoentrainment), light-induced melatonin suppression, and the post-illumination pupillary reflex (PIPR). Together, these results suggest that activation of MORs in the ipRGCs by opioid use and/or MOUDs may impair downstream ipRGC functions. This multi-disciplinary study will examine the novel overarching hypothesis that persistent alterations in sleep/wake behavior in OUD patients undergoing treatment are mediated by impaired ipRGC function, and biomarkers of this pathway can predict recovery and relapse. Three aims will be tested in a sample of 200 participants, 150 of whom will be engaged in MOUD therapy (e.g., 50 each on methadone, buprenorphine, and XR-NTX, respectively) and 50 of whom will be non-opioid using control participants. Aim 1 will test the hypothesis that MOUD differentially impacts function of ipRGC responses. Aim 2 will examine whether MOUD differentially impacts daytime sleepiness, daily sleep-wake behavior, sleep architecture, and sleep-disordered breathing. Finally, Aim 3 will determine if ipRGC function predicts opioid relapse among MOUD groups at 1-, 3- and 6- month follow-up. Compared to non-opioid using controls or persons receiving an opioid antagonist (XR-NTX), we predict that participants who are receiving an agonist (methadone) or partial-agonist (buprenorphine) MOUD will have the most ipRGC interference, as evidenced by reduced PIPR, attenuated light-induced melatonin suppression, reduced circadian rhythmic amplitude, increased sleep latency, and increased sleep fragmentation. Importantly, we hypothesize that impaired ipRGC function will predict worse treatment outcomes as indicated by opioid use by 6-month follow-up. Finally, an exploratory aim will examine whether the MOUD groups show different relationships between opioid craving/withdrawal symptoms and sleep-wake behavior over a 10-day assessment of the participants’ daily lives within the normal environment. The results of this study will be highly significant because it would support the use of the pupillary response to light and other indicators of ipRGC function as novel biomarkers to predict the response and outcomes to MOUDs.