Narcolepsy orexins

Zeitzer JM, Nishino S, Mignot E (2006) The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci 27 368-74... 

Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000 355 39-40. 

Brown, R. E. (2003). Involvement of hypocretins/orexins in sleep disorders and narcolepsy. Drug News Perspect. 16, 75-9. 

Chemelli, R. M., Willie, J. T., Sinton, C. M. et al. (1999). Narcolepsy in orexin knockout mice molecular genetics of sleep regulation. Cell 98, 437-51. 

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, may be caused by the lack of hypocretin mRNA and peptides in humans (Peyron et al., 2000) or a disruption of the hypocretin receptor 2 or its ligand in dogs and mice (Lin et al., 1999 Chemelli et al., 1999). Hypocretin-containing neurons are located exclusively in the dorsomedial, lateral, and perifornical hypothalamic areas (Peyron et al., 1998). Two hypocretin sequences, Hcrt-1 (orexin-A) and Hcrt-2 (orexin-B), are generated from a single preprohypocretin (De Lecea et al., 1998 Peyron et al, 1998 Sakurai et al, 1998). Axons from these neurons are found in the hypothalamus, locus coeruleus (LC), raphe nuclei, tuberomamillary nucleus, midline thalamus, all levels of spinal cord, sympathetic and parasympathetic centers, and many other brain regions... 

Other activators of the histaminergic system may also be involved in wakefulness. The orexin (i.e. hypocretin) A and B neuropeptides were isolated from rat hypothalamic extracts. A mutation in the orexin-2 receptor gene was found to be associated with canine narcolepsy, and mice lacking the orexin peptide display increases in REM and NREM sleep and a decrease in wakefulness time during the active period of normal rodents. However, the exact role of orexin in physiological sleep and the mechanisms involved have not yet been elucidated. 

Hungs, M. Mignot, E. (2001). Hypocretin/orexin, sleep and narcolepsy. Bioessays 23, 397-408. 

Orexins in sleep and wakefulness rodent models of narcolepsy-cataplexy... 

The cause of the orexin-containing cell loss in typical narcolepsy-cataplexy remains unknown, but the HLA association is intriguing because it suggests that autoimmunity could mediate a central disease process. This is not... 

The phenotypic characterization of genetically modified rodents has advanced the understanding of both the basis of narcolepsy-cataplexy and the functions of the orexin system in the normal animal. Here we review the... 

Severe narcolepsy-cataplexy indistinguishable from orexin mice... 

Although human narcolepsy is not typically associated with orexin gene mutations, the orexin / model is most similar to the case of a narcoleptic-cataplectic child, severely symptomatic from infancy, who has a genetic defect in orexin production and release (Peyron et al., 2000). Thus, constitutive orexin deficiency alone in the presence of otherwise histologically normal orexin neurons... 

Characterization of the receptor knockout mice (OXjR / and 0X2R l ) provided important information about the differential roles of the two receptors in both vigilance state control and the symptoms of narcolepsy (Kisanuki et al., 2000 Willie et al., 2003). In contrast to the direct transitions to REM sleep and abrupt behavioral arrests that characterized orexin mice, 0X,R l mice exhibited no direct transitions to REM sleep and only a modest decrease in REM sleep latency (Kisanuki et al, 2000). 0XiR / mice also showed slight fragmentation of vigilance states when compared with the normal animals (Kisanuki et al., 2000). 

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