Acute and persistent sex-dependent disruptions of sleep-wake architecture induced by fentanyl self-administration in mice.

Chronic opioid use is associated with profound sleep disturbances that may contribute to relapse in opioid use disorder (OUD). However, how opioid self-administration and abstinence alter sleep architecture in a sex-dependent manner remains poorly understood. Here, we examined the effects of volitional fentanyl intravenous self-administration (IVSA) on sleep-wake architecture in male and female mice across drug-taking and abstinence phases. Continuous home-cage monitoring revealed sex differences in baseline sleep, with females exhibiting increased wakefulness and reduced NREM sleep relative to males across conditions. Fentanyl IVSA increased dark-phase NREM sleep following self-administration sessions, whereas abstinence was characterized by a persistent reduction in REM sleep accompanied by increased REM bout frequency, indicative of REM fragmentation. Correlational analyses between sleep architecture and IVSA behavior revealed that higher fentanyl intake was associated with reduced sleep, particularly in females, in contrast to the positive sleep-intake relationship observed in saline controls. Principal component analysis identified a primary sleep component that captured fentanyl-related alterations in sleep-behavior relationships and a secondary component reflecting sex-dependent variation in sleep architecture. Together, these findings demonstrate that fentanyl self-administration induces both acute and enduring, sex-specific disruptions in sleep architecture that persist into abstinence and are associated with drug-seeking behavior. These results highlight sleep as a potential mechanistic contributor to relapse vulnerability and a promising therapeutic target in OUD.