Lessons from sleepy mice: Narcolepsy-cataplexy and the orexin neuropeptide system

Jon T. Willie, Masashi Yanagisawa

Research output: Chapter in Book/Report/Conference proceedingChapter


Narcolepsy-cataplexy consists of two underlying problems: (i) inability to maintain wakefulness, and (ii) intrusion of features of REM sleep into wakefulness or at sleep onset. Together these result in the symptom complex of excessive daytime sleepiness accompanied by irresistible “sleep attacks,” cataplexy, sleep-onset hallucinations, and sleep paralysis. A reliable diagnostic sign is that of “sleep-onset REM sleep” (SOREM) periods during polysomnographic recordings of daytime naps. Narcolepsycataplexy, in the vast majority of human cases, results from selective loss of hypothalamic neurons containing orexin (hypocretin) neuropeptides, possibly by an autoimmune process. The neuropeptides orexin-A and orexin-B are products of the prepro-orexin (prepro-hypocretin) gene that is expressed by a population of neurons in the lateral hypothalamic area (LHA). Notably, orexin neurons send projections throughout the brain and spinal cord with particularly dense innervations of monoaminergic and cholinergic centers controlling sleep-wake in the forebrain and brainstem. Orexin peptides are endogenous ligands for two G protein-coupled receptors termed orexin receptors type 1 and type 2 (OX1R and OX2R), and a number of studies have suggested that orexin peptides are primarily neuroexcitatory. OX1Rs exhibit moderately higher affinity for orexin-A while OX2Rs exhibit equal affinity for both orexin-A and orexin-B. The differential distribution of the two orexin receptors suggests distinct roles of each receptor in aspects of vigilance state control and muscle tone.

Original languageEnglish (US)
Title of host publicationNarcolepsy and Hypersomnia
PublisherCRC Press
Number of pages22
ISBN (Electronic)9781420019254
ISBN (Print)9780849337154
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Medicine(all)


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