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

Hypothalamic excitatory hypocretin (orexin) neurons have been discovered in 1998 and found to have widespread projections to basal forebrain, monoaminergic and cholinergic brainstem, and spinal cord regions. The hypocretin system is influenced both neuronally (e.g. suprachiasmatic nucleus, GABAergic, cholinergic and aminergic brainstem nuclei) as well as metabolically (e.g. glucose, ghrelin, and leptin). Physiologically the hypocretin system has been implicated in the regulation of behaviours that are associated with wakefulness, locomotion, and feeding. A role in REM sleep, neuroendocrine, autonomic and metabolic functions has also been suggested. 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.