You may remember that orexin is a small protein (peptide) released in the brain, which was originally identified because it stimulates feeding. In addition to a role in feeding/energy regulation, it is also critical in wakefulness. People with narcolepsy have very low (to undetectable) levels of orexin in their cerebral-spinal fluid (CSF). Notably, the only other disorder that has been associated with low orexin in the CSF to date (and it has only been tested in a couple of individuals) is PWS.

In this article just published in the Proceedings of the National Academy of Sciences USA, the authors made a mouse model of narcolepsy in which neurons secreting orexin were destroyed. They then showed that replacing the orexin (by direct injection into the brain) restored wakefulness. This is a strong demonstration that orexin is mediating the wakefulness in the animals. The authors conclude that drugs aimed at stimulating the orexin receptor (presumably some are currently under development) should improve wakefulness in those with narcolepsy and other disorders (eg, PWS) that are associated with daytime sleepiness. (They did not look at whether the mice ate more).

Michihiro M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice PNAS 101: 4649-4654, 2004

(full article available for free at the PNAS website)br />

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