Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

•The C57BL/6J mouse is a preclinical model for sleep apnea.•The C57BL/6J mouse is a preclinical model for apneas in sleep.•An orexin 2 receptor agonist reduces apnea in sleep as well as in wakefulness, independent of effects on sleep-wake state.•Results are a small step in the development of pharmacologic approaches to the treatment of apnea.

BackgroundThe hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing.MethodsIn C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/h during sleep–wake states at baseline and with an intracerebroventricular administration of vehicle, 4 nMol of agonist OBDL, and 4 nMol of an antagonist, TCS OX2 29.ResultsA significant reduction (p = 0.035, f = 2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p = 0.03, f = 3.8), NREM (p = 0.003, f = 6.98) and REM (p = 0.03, f = 3.92) with the agonist reducing the rate of apneas during sleep from 29.7 ± 4.7 (M ± SEM) to 7.3 ± 2.4 during sleep (p = 0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels.ConclusionsThe B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4 nMol given intracerebroventricularly will reduce events in sleep and also wakefulness.