Divergent ventilatory responses during opioid-induced respiratory depression in response to repeated fentanyl use

Opioid-induced respiratory depression (OIRD) is the hallmark of opioid overdose and a major risk factor for death due to fentanyl use. Although repeat opioid use (ROU) elevates the risk of death, understanding its influence over breathing and its control has been poorly resolved. We developed a mouse model of recurrent fentanyl use over 5 days to examine how ROU impacts breathing and activity from the pre-Bötzinger complex (preBötC), the brainstem network driving inspiratory rhythmogenesis. Initial fentanyl use caused a profound metabolic crisis during OIRD involving a mismatch between ventilation and oxygen consumption. By <i>day 5</i> of ROU, 77% of mice exhibited an adaptive ventilatory response following ROU, which was accompanied by an improved relationship between ventilation and oxygen consumption during OIRD. However, in the remaining minority, the adaptive response during OIRD failed to emerge following ROU. This divergence emphasizes the heterogeneity in ventilatory and metabolic outcomes following ROU. Moreover, following ROU, rhythmogenesis in the preBötzinger complex was less sensitive to mu-opioid receptor agonism, indicating that adaptation to ROU involves centrally mediated changes in this brainstem network. These findings reveal a series of physiological changes following ROU, typically resulting in improved ventilation and oxygenation during OIRD. Such changes, or lack of thereof, may contribute to the unpredictable nature of overdose susceptibility among opioid users.<b>NEW & NOTEWORTHY</b> Recurring fentanyl use is a significant factor contributing to opioid-related deaths, yet the physiological impact of repeat opioid use on breathing remains poorly understood. This study demonstrates that divergent ventilatory responses to opioids emerge following repeated fentanyl administration. These responses coincide with changes in oxygen consumption and inspiratory rhythmogenesis from the preBötzinger complex. These observations advance an understanding of the physiological basis for susceptibility and tolerance among individuals likely to succumb to opioid overdose.