["Acta Physiologica, Volume 242, Issue 6, June 2026. ", "\nABSTRACT\n\nAim\nOpioid‐induced respiratory depression (OIRD) is the leading cause of death following opioid overdose, due to its effects on central rhythm generation, and airway and thoracic constriction. While the effects on rhythm generation have been well documented, the effects of fentanyl on airway constriction are less well understood. We tested the hypothesis that the lower airways uniquely contribute to fentanyl‐induced airway constriction and may provide a potential additional therapeutic target for overdose reversal.\n\n\nMethods\nUrethane‐anesthetized mice were mechanically ventilated while pressure and airflow signals were recorded in vivo before and following intraperitoneal injection of fentanyl (500 μg/kg). The effects of naloxone, salbutamol, atropine, and positive‐end expiratory pressure (PEEP) were evaluated to determine the extent of lower airway contributions to airflow obstruction during overdose.\n\n\nResults\nIn addition to fentanyl's known depressive effects on respiratory drive, the introduction of fentanyl further disrupted airway patency by increasing dynamic resistance and decreasing lung compliance. These effects on respiration were not observed with naloxone alone and were reversed through administration of salbutamol, atropine, or introduction of PEEP. Importantly, opioid reversal with naloxone also produced a transient overshoot in dynamic resistance and lung compliance immediately following administration. We also observed an increase in physiological sighing following opioid removal.\n\n\nConclusions\nThe lower airways contribute to fentanyl‐induced airway constriction and serve as a potential additional therapeutic target following overdose. Fast‐acting pharmacological agents may be used in tandem with naloxone to reduce changes in dynamic resistance and lung compliance produced by fentanyl while also limiting any adverse effects of naloxone itself.\n\n"]