Spontaneous oxycodone withdrawal disrupts sleep, circadian, and electrophysiological dynamics in rats

Opioid dependence is defined by an aversive withdrawal syndrome upon drug cessation that can motivate continued drug-taking, development of opioid use disorder, and precipitate relapse. An understudied but common opioid withdrawal symptom is disrupted sleep, reported as both insomnia and daytime sleepiness. Despite the prevalence and severity of sleep disturbances during opioid withdrawal, there is a gap in our understanding of their interactions. The goal of this study was to establish an in-depth, temporal signature of spontaneous oxycodone withdrawal effects on the circadian composition of discrete sleep stages and the dynamic spectral properties of the electroencephalogram (EEG) signal in male rats. We continuously recorded EEG and electromyography (EMG) signals for 8 d of spontaneous withdrawal after a 14-d escalating-dose oxycodone regimen (0.5 - 8.0 mg/kg, 2xd; SC). During withdrawal, there was a profound loss and gradual return of circadian structure in sleep, body temperature, and locomotor activity, as well as increased sleep and wake fragmentation dependent on lights on/off. Withdrawal was associated with significant alterations in the slope of the aperiodic 1/f component of the EEG power spectrum, an established biomarker of arousal level. Early in withdrawal, NREM exhibited an acute flattening and return to baseline of both low (1-4 Hz) and high (15-50 Hz) frequency components of the 1/f spectrum. These findings suggest temporally dependent withdrawal effects on sleep, reflecting the complex way in which the allostatic forces of opioid withdrawal impinge upon sleep and circadian processes. These foundational data based on continuous tracking of nocturnal rhythms, sleep stage composition, and spectral EEG properties provide a detailed construct with which to form and test hypotheses on the mechanisms of opioid-sleep interactions.