What question did this study set out to answer?

This study aims to understand how enhanced vagal output contributes to airway obstruction induced by fentanyl during opioid overdose.

May 14, 2026

Fentanyl disrupts vagal control of the airways to induce transient obstruction

Puntos clave

This study aims to understand how enhanced vagal output contributes to airway obstruction induced by fentanyl during opioid overdose.
In-vivo recordings of diaphragm EMG, respiratory airflow, and vagus nerve activity in urethane-anesthetized mice before and after fentanyl administration (500 μg/kg).
Investigation of vagal pathways using bilateral vagotomy and atropine administration, and central opioid receptor mechanisms through intracisternal naloxone.
Analysis of the correlation between vagal activity and severity of airway obstruction.
Fentanyl induced a slowing of the respiratory rate with a compensatory increase in tidal volume and a transient delay between diaphragm activation and airflow onset.
Bilateral vagotomy or atropine abolished the delay caused by fentanyl, while intracisternal naloxone reversed it, indicating central vagal involvement.
Increased tonic vagal activation correlated significantly with the severity of airway disruption.

Resumen

Opioid-induced respiratory depression (OIRD) is the leading cause of death in opioid overdose. It reflects both a suppressed respiratory rhythm and heightened airway obstruction and thoracic rigidity, which together impair ventilation and resuscitation. While the effect(s) of opioids on central rhythm-generating circuits are well documented, the mechanisms leading to obstruction remain poorly understood. We investigated how enhanced vagal parasympathetic output contributes to fentanyl-induced airway disruption. We evaluated the contribution of vagal pathways and central opioid receptor mechanisms using bilateral vagotomy, atropine administration, and intracisternal naloxone administration. In urethane-anesthetized mice, diaphragm electromyography (EMG), respiratory airflow, and vagus nerve activity were recorded in-vivo before and after intraperitoneal fentanyl (500 μg/kg). We found that fentanyl caused a characteristic slowing of respiratory rate accompanied by a compensatory increase in tidal volume, but also produced a transient delay between diaphragm activation and airflow onset, consistent with airway obstruction. This delay was abolished by bilateral vagotomy or atropine and reversed by intracisternal naloxone administration, implicating central vagal mechanisms. Vagal electroneurograms showed increased tonic multiunit activity and enhanced large-amplitude single-unit firing, particularly within efferent fibers, together with a loss of normal inspiratory phase-locking. The magnitude of tonic vagal activation strongly correlated with the severity of airway disruption. From this we conclude that fentanyl disrupts respiratory-autonomic integration by enhancing parasympathetic vagal drive, producing a central, opioid receptor-mediated mechanism of airway constriction. Targeting vagal pathways may therefore represent a promising adjunctive strategy for improving airway patency and ventilatory recovery during opioid overdose reversal. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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