Hypocretins (orexins) and sleep–wake disorders

Summary Since their discovery in 1998, the hypocretins (orexins)—peptides that are produced by a group of neurons situated in the posterolateral hypothalamus—have been shown to excite many CNS areas including many neuronal systems that regulate sleep and wakefulness. Animal studies indicate that hypocretins play a part in the regulation of various functions including arousal, muscle tone, locomotion, regulation of feeding behaviour, and neuroendocrine and autonomic functions. A link between hypocretin deficiency and narcoleptic symptoms was first shown in canine and rodent models of narcolepsy. Hypocretin deficiency, as shown by low or absent concentrations in CSF, was subsequently found in 90% of patients with sporadic narcolepsy-cataplexy, and less commonly in familial narcolepsy. In most other sleep–wake and neurological disorders, hypocretin concentrations are normal. Low concentrations were also found in hypothalamic disorders, acute traumatic brain injury, and a few other disorders. The exact function of the hypocretin system in sleep–wake regulation and its pathophysiological role in hypocretin-deficient and non-deficient narcolepsy as well as in non-narcoleptic, hypocretin-deficiency syndromes remain unclear