INTRODUCTION The hypocretins/orexins are neuropeptides synthesized by a small neuronal cell group located in the posterior and lateral hypothalamus. These peptides have been considered modulators of the sleep-wakefulness cycle since their discovery in 1998; the hypocretinergic/orexinergic system is very active during wakefulness. In addition, the absence of either these peptides or their receptors is associated to narcolepsy-cataplexy, a disease in which the sleep-wakefulness cycle is completely disorganized. DEVELOPMENT. Hypocretinergic/orexinergic neurons directly activate the cerebral cortex and neuronal cell groups of the reticular activating system containing noradrenaline, serotonin, dopamine, acetylcholine and histamine, through which they may also indirectly activate the cerebral cortex and enhance wakefulness; as well, these neurons inhibit REM sleep generation in the ventral pontine tegmentum. The decrease in the activity of hypocretinergic/orexinergic neurons during sleep inhibits the aminergic and cholinergic neurons of the reticular activating core, decreasing cortical activation and renewing REM sleep generation in the ventral pontine tegmentum.
CONCLUSIONS Hypocretins/orexins modulate wakefulness and EEG activation in part through their actions on reticular core neurons projecting to the cortex and suppress REM sleep generation through inhibition of ventral pontine tegmentum neurons within the ventral oral pontine tegmentum. The hypoactivity of this system supports the sleep cycle fragmentation and general disorganization appearing in narcolepsy, as well as momentary interruption of wakefulness by REM sleep episodes.