Spontaneous Oxycodone Withdrawal Disrupts Sleep, Circadian, and Electrophysiological Dynamics in Rats

Abstract

Chronic usage of opioids can result in the development of highly aversive withdrawal symptoms such as dysphoria, increased pain sensitivity and sleep disturbances/insomnia. Experiencing these symptoms during chronic opioid administration is thought to facilitate development of opioid use disorder; a debilitating disorder characterized by escalating, compulsive drug use despite harmful consequences, a constellation of aversive withdrawal signs, cravings, relapse and an increased risk of death. Despite a growing body of research suggesting that opioid withdrawal can disrupt sleep, and produce insomnia or daytime sleepiness, opioid related sleep disturbances have not been rigorously characterized. Therefore, there is a gap in our understanding of how sleep disturbances manifest throughout chronic opioid administration and withdrawal. The goal of this study was to establish an in-depth, temporal characterization of how oxycodone withdrawal affects sleep. Rats were made dependent on the prescription opioid oxycodone via subcutaneously implanted drug pumps that delivered two oxycodone or saline infusions per day (ZT hours 0-2 and 12-14) in escalating doses for 14 days. Upon cessation of oxycodone delivery, somatic withdrawal signs such as ptosis, teeth chattering, head bobs, repetitive sniffing, and flattened posture emerged spontaneously. Electroencephalogram (EEG) and electromyogram signals were wirelessly and continuously recorded for the 14-day oxycodone regimen and for 8 days of spontaneous withdrawal. During withdrawal, there was a profound loss of diurnal rhythms of sleep stages [i.e., rapid eye movement (REM), non-REM (NREM), and Wake], temperature, and locomotor activity that returned to baseline levels after several days. Sleep stage fragmentation also increased. From EEG spectral analysis, I found that the daily rhythmicity of relative NREM power across multiple frequency bands was dampened, and the slope of the NREM EEG power spectrum was flattened suggesting an increase in local non-oscillatory activity. Together, these data provide temporal and mechanistic explanations for the clinical descriptions of “insomnia” and “daytime sleepiness” that are self-reported by opioid-dependent people during withdrawal. Given the large literature on the gradual emergence of aversive withdrawal signs during chronic opioid administration, I performed exploratory analyses of sleep architecture and dynamics data collected during the 14-d escalating-dose oxycodone regimen. The loss of daily sleep rhythmicity and structure observed during withdrawal began to emerge after 3-7 days of oxycodone infusions. In contrast, withdrawal-associated disruptions in EEG spectral properties did not emerge during oxycodone administration. These findings suggest that the allostatic forces of chronic opioids and withdrawal impact sleep through neuroadaptations in diverse neural circuits. In summary, these foundational data provide a detailed construct with which to form and test hypotheses on the mechanisms of opioid-sleep interactions.