Biological sex influences sleep phenotype in mice experiencing spontaneous opioid withdrawal

Abstract

SummaryAversive symptoms, including insomnia experienced during opioid withdrawal, are a major drive to relapse; however, withdrawal‐associated sleep symptomatology has been little explored in preclinical models. We describe here a model of opioid withdrawal in mice that resembles the sleep phenotype characteristic of withdrawal in humans. Male and female C57BL/6 mice were instrumented with telemeters to record electroencephalogram, electromyogram, activity and subcutaneous temperature. All mice received two treatments separated by a 16‐day washout period: (1) saline (volume: 10 ml kg−1); or (2) ascending doses of morphine (5, 10, 20, 40 and 80 mg kg−1; volume: 10 ml kg−1) for 5 days at Zeitgeber time 1 and Zeitgeber time 13. Recordings for the first 71 hr after treatment discontinuation (withdrawal days 1–3) and for 24 hr on withdrawal days 5 and 7 were scored for sleep/wake state, and sleep architecture and electroencephalogram spectral data were analysed. Morphine was acutely wake‐ and activity‐promoting, and non‐rapid eye movement and rapid eye movement sleep were increased during the dark phase on withdrawal day 2 in both sexes. While non‐rapid eye movement delta power (0.5–4.0 Hz), a measure of sleep intensity, was reduced during the light phase on withdrawal day 1 and the dark phase on withdrawal day 2 in both sexes, female mice also exhibited changes in the duration and the number of bouts of sleep/wake states. These observations of fragmented sleep on withdrawal days 1–3 suggest poorer sleep consolidation and a more pronounced withdrawal‐associated sleep phenotype in female than in male mice. These data may indicate a greater sensitivity to morphine, a more distinct aversive sleep phenotype and/or a faster escalation to dependence in female mice.