Opioid-induced sleep disruption in C57BL/6J mice: A systems physiology perspective

This dissertation was motivated by the ongoing opioid epidemic and the substantial impact of opioids on sleep health. While opioids are well-documented sleep disruptors, their effects on sleep have been understudied. Sleep plays a key role in overall health, and is closely interrelated to many other physiological systems, including motor activity control and body temperature regulation.

The chapters of this dissertation investigate the dose-dependent effects of morphine and fentanyl on sleep amount and architecture. Given that sleep homeostasis is a tightly regulated and multifactorial process, this work also examines the dose-dependent effects of opioids on EEG power, motor activity, and body temperature. Although the dependent variables observed here have been studied previously, they are often studied independently. This dissertation adopts an integrative approach to investigate the interaction among the effects of opioids on sleep, motor activity, and body temperature. To address these objectives, male B6 mice were used to simultaneously record sleep/wake states, motor activity and subcutaneous body temperature. The interactions among the dependent variables were evaluated through mediation analysis, a statistical approach based on structural equation modeling.

Chapters 2 and 3 detail the effects of antinociceptive doses of opioids on sleep and EEG. Chapter 3 expands on this by exploring the dose-dependent effects and depicting four-point logarithmic dose-response curves of the effects of fentanyl and morphine on sleep, EEG power, motor activity and body temperature.

The findings presented in this dissertation offer novel insights into the mechanisms underlying opioid-induced sleep disruption, suggesting that in B6 mice this disruption is at least partially secondary to the opioid-induced increases in motor activity. Taken together, this work provides a new perspective through an integrative approach commonly used in systems physiology. The results shown here also underscore the importance of evaluating together opioid-induced adverse effects to better inform new strategies for the management of opioid-induced sleep disruption, pain management, addiction and overall opioid use.