Bidirectional Relationship between Opioids and Disrupted Sleep: Putative Mechanisms

D Eacret, S C Veasey, J A Blendy, D Eacret, S C Veasey, J A Blendy

Abstract

Millions of Americans suffer from opiate use disorder, and over 100 die every day from opioid overdoses. Opioid use often progresses into a vicious cycle of abuse and withdrawal, resulting in very high rates of relapse. Although the physical and psychologic symptoms of opiate withdrawal are well-documented, sleep disturbances caused by chronic opioid exposure and withdrawal are less well-understood. These substances can significantly disrupt sleep acutely and in the long term. Yet poor sleep may influence opiate use, suggesting a bidirectional feed-forward interaction between poor sleep and opioid use. The neurobiology of how opioids affect sleep and how disrupted sleep affects opioid use is not well-understood. Here, we will summarize what is known about the effects of opioids on electroencephalographic sleep in humans and in animal models. We then discuss the neurobiology interface between reward-related brain regions that mediate arousal and wakefulness as well as the effect of opioids in sleep-related brain regions and neurotransmitter systems. Finally, we summarize what is known of the mechanisms underlying opioid exposure and sleep. A critical review of such studies, as well as recommendations of studies that evaluate the impact of manipulating sleep during withdrawal, will further our understanding of the cyclical feedback between sleep and opioid use. SIGNIFICANCE STATEMENT: We review recent studies on the mechanisms linking opioids and sleep. Opioids affect sleep, and sleep affects opioid use; however, the biology underlying this relationship is not understood. This review compiles recent studies in this area that fill this gap in knowledge.

Copyright © 2020 by The Author(s).

Figures

Fig. 1.
Fig. 1.
Opioid-related wake-promoting vs. opioid-related sleep-promoting systems. These regions and cell types have been shown in this review to be related to opioids and affect sleep. The wake-promoting systems are generally activated by opioids, and the sleep-promoting systems are generally inhibited by opioids.
Fig. 2.
Fig. 2.
Neural circuitry of reward/opioid regions involved in sleep/wake. A likely circuit mechanism regulating sleep/wake states that are engaged by opioid use. This figure infers the sleep/wake circuitry in response to opioids. Green indicates wake-promoting systems and red indicates sleep-promoting systems. Many brain regions were tested for neuronal activation or inhibition, but not all were tested for opioid effects on sleep. VLPO and RMTg neurons are sleep-promoting and are inhibited by opioids. This VLPO opioid exposure inhibits sleep-promoting neurons to produce wakefulness, whereas RMTg opioid exposure disinhibits VTA dopamine neurons. Connections between brain regions are drawn for studies in this review that have manipulated projections and examined sleep. For the VLPO, and for adenosine 2A receptor neurons in the nucleus accumbens, experiments examined manipulation of those neurons specifically, and projections to other reward-related brain regions were not established. 5HT, 5-hydroxytryptamine. DA, Dopamine. DRN, Dorsal Raphe Nucleus.

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