Opioids Disrupt Sleep and Wakefulness in C57BL/6J mice

Opioid use disorder (OUD) is a major public health burden. According to the National Institutes of Health (NIH), studies helping to understand the mechanisms of OUD will help improve prevention and treatment. Opioids long have been shown to disrupt sleep and sleep disruption enhances the likelihood of addiction relapse in humans. The NIH refers to the mouse as one of the most powerful animal systems to study because of the genetic homologies between human and mouse. Prior to the present research, no studies have quantified the effect of opioids on states of sleep and wakefulness in mice. The current study was designed to test the hypothesis that acute administration of buprenorphine, morphine, or fentanyl disrupts sleep/wake architecture in C57BL/6J (B6) mice. Adult male mice (n = 8) were housed in a temperature-controlled environment and a 12:12 h light:dark cycle with ad libitum access to food and water. Mice were anesthetized with isoflurane for implantation of a telemeter (DSI HD-X02) and electrodes for wireless recording of cortical electroencephalogram (EEG) and dorsal neck muscle electromyogram (EMG). These signals were used to objectively quantify wakefulness, NREM sleep, and REM sleep in 10-s bins. Recordings began one week after the mice recovered from surgery and were performed within 1.5 h of light onset. Every mouse received at least one intraperitoneal injection (0.3 mL) each of saline (control) and an antinociceptive dose of buprenorphine, morphine, and fentanyl separated by one week. Each recording was scored independently by two individuals, one of whom was blinded to the treatment condition. Sleep scoring concordance scores were greater than 90%. These results, expressed as percent change from saline, summarize 64 recordings. The results show that buprenorphine significantly increased wakefulness (151% ;p=0.0078) and eliminated both NREM and REM sleep. Morphine significantly increased wakefulness (142% ;p=0.0078), decreased NREM sleep (-94% ;p=0.0078) and eliminated REM sleep. Fentanyl significantly increased wakefulness (105% ;p=0.0078), decreased NREM sleep (-68% ;p=0.0078) and decreased REM sleep (-89% ;p=0.0078). These results support the likelihood that studies of opioid effects on sleep using the B6 mouse will help provide a mechanistic understanding of opioid-induced sleep disruption in humans.