Locus Coeruleus activity correlates with transient elevations in breathing during opioid-induced respiratory depression

A history of use remains a key risk factor for opioid-related overdose deaths in the ongoing opioid epidemic. The locus coeruleus (LC) is the principal source of noradrenergic tone and a site for opioid neuromodulation and tolerance. How a history of opioid use affects LC activity and shapes opioid-induced respiratory depression (OIRD) remains poorly understood. Using plethysmography and fiber photometry, we assessed how fentanyl affects LC activity and OIRD before and after five days of repeat opioid use (ROU). Fentanyl increased the frequency of LC bursts independent of exposure history and was coupled to transient elevations in breathing. LC coupled ventilation (LC-Ve) persisted through ROU. After ROU, OIRD magnitude diverged across mice. Mice developing an adaptive ventilatory response (AVR) showed a smaller OIRD that coincided with improved ventilation outside LC bursts and reduced LC-Ve gain. Mice with the non-adaptive response (NVR) show no improvement in OIRD or ventilation outside LC bursts, resulting in an unchanged reliance on LC-Ve. While LC-Ve reflexively counters OIRD acutely, it may also drive oscillations to destabilize blood gas homeostasis, perpetuating pathophysiology with repeat use. Thus, LC-coupled breathing appears to be a physiological signature of divergent respiratory responses with a history of fentanyl exposure.