Spontaneous daily sleep disruptions associated with morphine dependence and withdrawal in rats

Sleep disturbances are prominent symptoms of opioid withdrawal that contribute to relapse in individuals with opioid use disorder (OUD). Although preclinical studies often examine protracted withdrawal after sustained abstinence, few address the repeated, spontaneous withdrawal cycles that model human patterns of use. Moreover, targeting sleep disruptions provides a novel strategy to reduce relapse risk. The present studies characterized the effects of repeated spontaneous daily withdrawal on sleep and quantitative electroencephalography (qEEG) after once-daily morphine administration in male Sprague-Dawley rats. Daily withdrawal produced persistent sleep disruptions, including reduced rapid eye movement (REM) and non-REM sleep, increased time awake, and sleep fragmentation. Notably, tolerance did not develop to the acute pharmacological effects of morphine or spontaneous daily withdrawal effects on sleep across the 30-day study. Relative spectral analysis (qEEG) revealed progressive shifts from low (δ) to high (γ) frequency power across withdrawal phases, with significant and persistent increases in wake and non-REM relative γ band power during later stages of daily and protracted withdrawal. There were few correlations between somatic behavioral signs and sleep or qEEG supporting our hypothesis that sleep, and brain activity disturbances represent distinct withdrawal phenotypes that should be studied and treated separately from somatic withdrawal behaviors. Together, these findings highlight the chronic and multifaceted nature of opioid withdrawal, particularly its effect on disrupted sleep and brain activity. Collectively, these studies characterized a translationally relevant preclinical model incorporating both sleep and qEEG as potential behavioral and physiological biomarkers for evaluating putative pharmacotherapies for withdrawal-related sleep dysfunction in OUD. SIGNIFICANCE STATEMENT: Sleep disruptions associated with withdrawal in opioid use disorder represent a contributing factor for relapse yet lack targeted treatments. This study reports consistent, spontaneous daily sleep disruptions in rats after once-daily morphine administration, providing a model that can be used for treatment development.