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

治疗阿片类药物使用障碍的药物差异调节本质光敏性视网膜神经节细胞功能、睡眠和昼夜节律：对治疗的影响

• 批准号: 10783274
• 负责人: Karen L Cropsey
• 金额: $ 110.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10783274
• 关键词: Acute; Affect; Agonist; Arousal; Attenuated; Behavior; Biological Markers; Brain; Buprenorphine; Cell physiology; Chronic; Circadian Dysregulation; Circadian Rhythms; Darkness; Data; Drowsiness; Drug Prescriptions; Electrophysiology (science); Environment; Excessive Daytime Sleepiness; FDA approved; Genetic; Human; Impairment; Income; Intervention; Light; Lighting; Macaca mulatta; Mediating; Medical; Melatonin; Methadone; Moods; Naltrexone; Neurons; Opioid; Opioid Antagonist; Opioid agonist; Outcome; Participant; Pathway interactions; Patients; Periodicity; Persons; Pharmaceutical Preparations; Productivity; Pupil; Pupil light reflex; Quality of life; Recovery; Relapse; Reporting; Retina; Retinal Ganglion Cells; Rodent; Safety; Sampling; Selection for Treatments; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Testing; Treatment outcome; United States; Ventilatory Depression; Vision; Withdrawal; Withdrawal Symptom; Work; actigraphy; antagonist; awake; chronic pain; circadian; circadian regulation; cohort; craving; disorder control; economic cost; follow-up; ganglion cell; health care service utilization; illicit opioid; improved; improvement on sleep; individualized medicine; medication for opioid use disorder; mu opioid receptors; multidisciplinary; neural; non-opioid analgesic; novel; novel marker; opioid overdose; opioid use; opioid use disorder; opioid user; overdose death; preclinical study; predicting response; prescription opioid; response; selective expression; side effect; sleep regulation; societal costs; treatment response

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.

项目总结