Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter

Pathophysiologically a deficient hypocretin neurotransmission has been found in human narcolepsy and (engineered) animal models of the disorder. Different mechanisms are involved including (1) degeneration of hypocretin neurons (mice), (2) hypocretin ligand deficiency (humans, mice, dogs), (3) hypocretin receptor deficiency (mice, dogs). Reports of low hypocretin-1 cerebrospinal fluid levels in neurologic conditions (e.g. Guillain-Barré syndrome, traumatic brain injury, hypothalamic lesions) with and without sleep-wake disturbances and, on the other hand, observations of normal levels in about 11% of narcoleptics raise questions about the exact nature and pathophysiological base of the link between hypocretin deficiency and clinical manifestations in human narcolepsy.