Reversal of morphine-induced respiratory depression by doxapram in anesthetized rats

The present study was undertaken to investigate whether doxapram, a blocker of tandem pore K+ (TASK-1/−3) channels, is a useful tool for recovery from morphine-induced ventilatory disturbances. Spontaneous ventilation and the hind leg withdrawal response against noxious thermal stimulation were recorded simultaneously in anesthetized rats. Morphine (1.0 mg/kg, i.v.) decreased the minute volume resulting from depression of the ventilatory rate and tracheal airflow. Concomitantly, it prolonged the latency of withdrawal response against the thermal stimulation. Subsequent intravenous injection of doxapram recovered the morphine-induced ventilatory depression. This effect of doxapram declined rapidly after a single injection (1.0–3.0 mg/kg, i.v.) but persisted with a continuous infusion (0.33 mg/kg/min). Neither single injection nor continuous infusion of doxapram had any detectable effect on the analgesic potency of morphine. The central respiratory activity was recorded from the phrenic nerve in anesthetized, vagotomized, paralyzed and artificially ventilated rats. Morphine (3.0 mg/kg, i.v.) induced respiratory depression, characterized by a prolonged plateau-like inspiratory discharge (apneustic discharge) in the phrenic nerve. Doxapram (10 mg/kg, i.v.) restored the morphine-induced apneustic discharge to an augmenting inspiratory discharge. This study demonstrated that doxapram counteracted morphine-induced respiratory depression by stimulating the central respiratory network without compromising morphine antinociception. These results support the clinical use of doxapram for amelioration of ventilatory disturbances in patients treated with opioids.