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Narcolepsy has puzzled neurologists for more than a century. The combination of daytime sleepiness and spells of muscle weakness with laughter1 was unexplained until 1960, when it was recognized that narcolepsy is associated with premature onset of REM sleep.2 A further advance in understanding the disease was the discovery that narcolepsy is strongly associated with a specific human leukocyte antigen (HLA) serotype, now recognized as HLA DQB1*0602.3 The major breakthrough, however, occurred in the last 2 years and is a fascinating story of scientific discovery.
In 1999, two peptides were identified in the hypothalamus and were named hypocretin- (Hcrt-) 1 and 2,4 reflecting their hypothalamic origin and homology to secretin. This is the terminology we will use here. Another group of investigators independently identified the same peptides, which they named orexin A and B, based on their appetite-stimulating effects.5 These molecules arise from a precursor, preprohypocretin, synthesized by a small number of cells in the posterior and lateral hypothalamus, especially the perifornical area. They project to a diverse set of targets in the brain and spinal cord, especially the monoaminergic and cholinergic components of …
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