Dose-dependent, opioid-induced sleep disruption is partially mediated by motor activity but not by body temperature...

States of sleep and wakefulness, motor activity, and body temperature are temporally linked, yet these variables are often studied independently. Here, we report novel results from male C57BL/6J mice (n = 24) that quantify the causal and correlational relationships between these temporally linked measures. The initial experiments used 12 mice to identify the lowest antinociceptive doses of fentanyl (0.1 mg/kg) and morphine (1 mg/kg). Twelve additional mice were implanted with telemeters to simultaneously record electroencephalogram, electromyogram, motor activity, and subcutaneous body temperature. Doses of fentanyl (0.1, 0.3, 1, 3 mg/kg) and morphine (1, 3, 10, 30 mg/kg) caused significant (P < .05) increases in wakefulness and decreases in non-rapid eye movement and rapid eye movement sleep. Fentanyl (0.1-3 mg/kg) and morphine (3-30 mg/kg) significantly increased motor activity. Body temperature during wakefulness was significantly decreased by fentanyl (1 and 3 mg/kg). Morphine increased (3 mg/kg) and decreased (30 mg/kg) body temperature. Mediation analyses showed that the increase in wakefulness caused by fentanyl and morphine was partially mediated by motor activity but not by changes in body temperature. These results provide the first complete dose-response data for the effects of fentanyl and morphine on simultaneously acquired measures of sleep/wake states, body temperature, and motor activity. Compared with human data, these results from mice reveal similarities (sleep disruption, hyperthermia and hypothermia, muscle rigidity) and differences (increased motor activity) caused by fentanyl and morphine. The results also demonstrate the power of mediation analyses for providing nuanced insights into opioid effects on clinically relevant neurobehavioral phenotypes. SIGNIFICANCE STATEMENT: This study demonstrated that in mice, even the lowest doses of fentanyl and morphine that caused antinociception also caused sleep disruption. Thus, in mice, it is not possible to provide antinociception using fentanyl or morphine without causing sleep disruption.