Fentanyl-Induced Diaphragmatic Discoordination during Overdose

Synthetic opioids like fentanyl are a leading cause of overdose mortality. Although the hallmark of fentanyl overdose is ventilatory depression, fentanyl also induces tonic activation of skeletal musculature, including the diaphragm, which may advance progression of overdose towards death. While tonicity may further restrict diaphragmatic contractility, phase-specific dysregulation may also reflect a larger state of discoordination in respiratory control. Using urethane-anesthetized mice exposed to fentanyl, we test the hypothesis that fentanyl-induced diaphragm tonicity results from a loss of coordinated motor activity. Fentanyl produced two distinct phases: an initial phase of maximal ventilatory depression with preserved phasic activity, and a later phase characterized by unstable ventilation that partially rebounds, tonic diaphragmatic activation with loss of inspiratory phase dominance in EMG activity, and diminished bilateral diaphragmatic coordination. Carotid body denervation eliminated tonic activity and expiratory-phase EMG elevation, but it did not prevent hemi-diaphragm discoordination or ventilatory instability. Rhythmic brainstem slice recordings showed that bilateral preBotzinger complex burst-amplitude coupling was disrupted by -opioid receptor (MOR) agonism. Furthermore, disordered diaphragm activity was reversed by administration of the MOR antagonist, naloxone. Our findings reframe fentanyl overdose as a temporally evolving syndrome that involves distinct mechanisms to disrupt respiratory motor coordination. SIGNIFICANCE STATEMENTRespiratory depression is the hallmark of fentanyl overdose. We demonstrate that fentanyl actively reorganizes motor control of breathing, resulting in aberrant diaphragmatic tonicity and a loss of bilateral coordination. These phenomena emerge in temporal sequence and are driven by distinct central and peripheral contributions, suggesting fentanyl overdose is a complex multistage process and may require unique intervention strategies at different stages.