Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys.

Abstract

Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia. Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats. Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg^-1 s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg^-1 s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg^-1 (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg^-1 s.c.) reversed fentanyl-induced increase in Pco₂ (P=0.006), and decrease in Po₂ (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg^-1 s.c. reversed fentanyl-induced increase in Pco₂ (P=0.007), and decrease in Po₂ (P=0.013) and SO₂ (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg^-1 s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models. Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.