Fig. 9.
Administration of a low dose of naloxone followed by varenicline reversed fentanyl-induced lethal apnea. All drugs were administrated bolus iv. Administration of a high dose of fentanyl (120 µg/kg) over a short period (1 min) induced lethal apnea. (A) Saline vehicle injection post fentanyl administration had no effects on profound, severe respiratory depression, apnea, and lethality. (B) Administration of a high dose of ABT 594 (30 µg/kg) reduced apneas and resulted in the recovery of respiratory rhythm and rat survival. (C) Administration of a high dose of naloxone (1 mg/kg) reduced apneas and resulted in a rapid recovery of respiratory rhythm and rat survival; the rat woke up within 4 min after naloxone administration, agitated. (D) Administration of a low dose of naloxone (1 µg/kg) had no marked effects on apneas and lethality. (E) Administration of a low dose of naloxone (1 µg/kg), followed by varenicline (1 mg/kg), reduced the period of apnea and induced the quick recovery of respiratory rhythm and survival. (F–H) Population data showing the time course of changes of minute ventilation (, relative to before fentanyl, F, G, median and interquartile ranges), and survival rate (H) in response to administration of lethal dose fentanyl (120 µg/kg) with postadministration of bolus saline, varenicline (1 mg/kg), ABT 594 (30 µg/kg), high doses of naloxone (0.03 to 1 mg/kg), low dose of naloxone (1 µg/kg), low dose of naloxone (1 µg/kg) followed by varenicline (1 mg/kg). *P < 0.05, statistically significant difference compared with saline group (F), compared with both saline and varenicline groups (G and H). Kruskal–Wallis one-way ANOVA on ranks (Tukey test), or Mann–Whitney rank sum test for analysis of in F; Kruskal–Wallis one-way ANOVA on ranks (Tukey test) for analysis of in G, z test for analysis of survival rate (H). n = 4 animals for each group.