Role of orexins

Extrahypothalamic OX-B-like immunoreactivity, reminiscent to that of CRF, has been described in clustered GABAergic neuronal populations, in the lateral division of central nucleus ofthe amygdala, the bednucleus of the stria terminalis, and in the hippocampus. Moreover, ectopic expression of preproorexin mRNA in the gut, ependymal cells, neuroblastomas, and of orexin receptors in adrenal gland, cancer and hematopietic stem cells suggests yet unexplored roles of orexins as paracrine factors controlling blood-brain barrier, and tumor or stem cell function. 

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. 

Hayaishi, O. Huang, Z. L. (2004). Role of orexin and prostaglandin E2 in activating histaminergic neurotransmission. Drug News Perspec. 17, 105-9. 

Mieda, M. Yanagisawa, M. (2002). Sleep, feeding, and neuropeptides roles of orexins and orexin receptors. Curr. Opin. Neurobiol. 12, 339-45. 

Sakurai T. (2005). Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med. Rev. 9, 231-41. 

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). 

The second constellation of narcoleptic symptoms can be summarized under the rubric of excessive daytime sleepiness, or an inability to regulate wakefulness. As recently reviewed by Mochizuki et al. (2004), at least four explanations have to date been proposed for this sleepiness a deficit in arousal, an impaired circadian alertness signal, abnormal homeostatic regulation of non-REM sleep, and excessive vigilance state fragmentation. These mechanisms are not mutually exclusive, and there are possible roles for orexin signaling in each of them, as we review in the following sections. 

Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci 2002 25 283-313. 

The physiological and pathophysiological role of presynaptic orexin receptors is incompletely understood, and drugs targeting orexin receptors so far have not been developed. Orexins play an important role in the control of sleep and wakefulness, as highlighted by the findings that the knockout of preproorexin in mice (Chemelli... 

Occasionally, narcolepsy results from mutations in orexin neuropeptides (also called hypocre-tins), which are expressed in the lateral hypothalamus, or in their G protein—coupled receptors. Although such mutations are not present in most subjects with narcolepsy, the levels of orexins in the CSF are diminished, suggesting that deficient orexin signaling may play a pathogenic role. 

Lesions of the lateral hypothalamic area (LHA) cause anorexia, whereas ablation of the paraventricular nucleus (PVN) cause a hyperphagic obesity syndrome. Consistent with these results, LHA neurons express the orexigenic neuropeptides MCH and orexin. PVN neurons produce several neuropeptides that are anorex-igenic when administered directly into the brain (CRH, TRH, oxytocin), in addition to their better known roles as endocrine regulators. LHA and PVN receive rich inputs from axons of NPY/AgRP and aMSH/CART-producing neurons in the arcuate nucleus. 

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