Dose-dependent, opioid-induced sleep disruption is partially mediated by motor activity but not by body temperature in C57BL/6J mice

Abstract 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 EEG, 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<0.05) increases in wakefulness and decreases in NREM and REM sleep. Fentanyl (0.1 to 3 mg/kg) and morphine (3 to 30 mg/kg) significantly increased motor activity. Body temperature during wakefulness was significantly decreased by fentanyl (1, 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 effects of fentanyl and morphine on simultaneously acquired measures of sleep/wake states, body temperature, and motor activity. Compared to human data, these results from mice reveal similarities (sleep disruption, hyperthermia and hypothermia) 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 Sleep disruption is an undesired, clinically significant effect of opioids prescribed to manage pain. Sleep disruption exacerbates pain and can lead to increased opioid requirement, as well as increased risk of addiction relapse. The significance of this study is the discovery 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. Competing Interest Statement The authors have declared no competing interest. Data Availability All the data supporting the findings of this paper are available within the paper. Abbreviations - EEG - electroencephalogram /electroencephalographic - B6 - C57BL/6J - Tsc - subcutaneous body temperature - EMG - electromyogram - REM - rapid eye movement - NREM - non-rapid eye movement - ED50: - half-maximal dose for increasing a response - ID50: - half-maximal dose for decreasing a response - ln - natural log