Orexins/
hypocretins are hypothalamic
neuropeptides that promote and stabilize wakefulness by binding to the
orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the
sleep disorder narcolepsy in mice, rats, dogs, and humans. The
orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas
suvorexant has been clinically approved for the treatment of
insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why
orexin receptor antagonists do not induce overt
narcolepsy-like symptoms. Here we show that acute and chronic
suvorexant promotes both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep without inducing
cataplexy in mice. Interestingly, chronic
suvorexant increases OX2R
mRNA and decreases
orexin mRNA and
peptide levels, which remain low long after termination of
suvorexant administration. When mice are chronically treated with
suvorexant and then re-challenged with the antagonist after a 1-week washout, however,
cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous
orexin knockout mice, with lower brain
orexin levels, show
cataplexy and SOREM after acute
suvorexant administration. Furthermore, we find that acute
suvorexant can induce
cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that
suvorexant can inhibit
orexin synthesis resulting in susceptibility to
narcolepsy-like symptoms in mice under certain conditions.