Orexins (also known as hypocretins) play critical roles in the regulation of 
sleep/wakefulness states by activating two G-protein coupled receptors (GPCRs), 
orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to understand the 
differential contribution of both receptors in regulating sleep/wakefulness 
states we compared the pharmacological effects of a newly developed OX2R 
antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor 
antagonist (DORA), suvorexant, in C57BL/6J mice. After oral administration in 
the dark period, both C1m and suvorexant decreased wakefulness time with similar 
efficacy in a dose-dependent manner. While C1m primarily increased total 
non-rapid eye movement (NREM) sleep time without affecting episode durations and 
with minimal effects on REM sleep, suvorexant increased both total NREM and REM 
sleep time and episode durations with predominant effects on REM sleep. 
Fos-immunostaining showed that both compounds affected the activities of 
arousal-related neurons with different patterns. The number of Fos-IR 
noradrenergic neurons in the locus coeruleus was lower in the suvorexant group 
as compared with the control and C1m-treated groups. In contrast, the numbers of 
Fos-IR neurons in histaminergic neurons in the tuberomamillary nucleus and 
serotonergic neurons in the dorsal raphe were reduced to a similar extent in the 
suvorexant and C1m groups as compared with the vehicle-treated group. Together, 
these results suggest that an orexin-mediated suppression of REM sleep via 
potential activation of OX1Rs in the locus coeruleus may possibly contribute to 
the differential effects on sleep/wakefulness exerted by a DORA as compared to a 
2-SORA.