Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

Abstract

In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

“…Recently, the U.S. Food and Drug Administration approved suvorexant (Belsomra; Merck, White House Station, NJ) for the treatment of insomnia (http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm409950.htm). It is now well established that selective OX2R antagonists have robust hypnotic activity in preclinical species, and transient pharmacological inhibition of the two receptors, either by a dual OX1/2R antagonist or by simultaneous blockade of OX1R to OX2R antagonism, disrupts sleep architecture by shifting the balance in favor of REM sleep at the expense of NREM sleep (Dugovic et al, 2014). The role of the OX1R in emotional behavior is starting to emerge .…”

“…In rats, the coadministration of the OX2R antagonist JNJ-10397049 [N-(2,4-dibromophenyl)-N9-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]-urea] and the OX1R antagonist SB-408124 or GSK-1059865 promoted REM sleep, whereas REM sleep was not affected by either OX2R or OX1R blockade alone (Dugovic et al, 2009(Dugovic et al, , 2014. Consistent with these data, we found that compound 56 was devoid of sleep-promoting effects under basal conditions in rats and WT mice.…”

“…Previous studies have demonstrated that OX1R antagonists minimally affect sleep-wake states in basal conditions (Smith et al, 2003;Dugovic et al, 2009Dugovic et al, , 2014Gozzi et al, 2011;Steiner et al, 2013a) but produce a disinhibition of REM sleep in the presence of OX2R antagonism (Dugovic et al, 2014). In rats, the coadministration of the OX2R antagonist JNJ-10397049 [N-(2,4-dibromophenyl)-N9-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]-urea] and the OX1R antagonist SB-408124 or GSK-1059865 promoted REM sleep, whereas REM sleep was not affected by either OX2R or OX1R blockade alone (Dugovic et al, 2009(Dugovic et al, , 2014.…”

“…Previous studies have demonstrated that OX1R antagonists minimally affect spontaneous sleep-wake states in rodents, but produce a disinhibition of REM sleep in the presence of OX2R antagonism (Dugovic et al, 2014). In the present study, the in vivo functional target engagement was investigated in a model of permanent inhibition of OX2R, and the effects of compound 56 on sleep-wake states were examined in mice lacking the OX2R relative to their corresponding wildtype (WT) mice.…”

“…Compound 56 was tritiated, tested as a tracer for autoradiography on rat tissue sections, and in vivo target engagement was measured after subcutaneous injection of compound 56 in rat brain using ex vivo receptor occupancy. We have recently shown that, although selective OX1R antagonism did not affect sleep-wake states, additional pharmacologic blockade of OX1R to OX2R antagonism elicited a disinhibition of rapid eye movement (REM) sleep at the expense of non-REM (NREM) sleep in rats (Dugovic et al, 2014). Therefore, the effect of the selective OX1R antagonist on sleep was tested in OX2R knockout (KO) mice to demonstrate in vivo functional target engagement.…”