Central chemoreception, the highly sensitive ventilatory response to small changes in CO(2)/pH, involves many sites. Hypothalamic orexin neurons are CO(2) sensitive in vitro, prepro-orexin knockout mice have a reduced CO(2) response prominently in wakefulness, and focal antagonism of the orexin receptor 1 (OX(1)R) in two central chemoreceptor sites, the retrotrapezoid nucleus (RTN) or the medullary raphé, results in a reduction of the CO(2) response predominately in wakefulness (-30% and -16%, respectively). Here we hypothesize that acute and selective inhibition of both orexin receptors (OX(1)R and OX(2)R) at all central locations by an orally administered dual orexin receptor antagonist, almorexant, will substantially attenuate the CO(2) response in a vigilance-state- and diurnal-cycle-dependent manner. We found that almorexant attenuated the CO(2) response by 26% only in wakefulness during the dark period of the diurnal cycle to a level observed during NREM sleep in the light period in controls suggesting that the sleep-wake difference in the CO(2) response can be in large part attributed to orexin. Almorexant also decreased wakefulness and increased NREM and REM sleep during the dark period, as previously reported, and unexpectedly decreased the number of sighs and post-sigh apnoeas during wakefulness in both the light and the dark period and during both wakefulness and NREM sleep in the dark period. The results support our hypothesis that the orexin system participates importantly in central chemoreception in a vigilance-state- and diurnal-cycle-dependent manner and indicate a role for orexin in the important process of sighing.