Orexin neuropeptide

Willie, J. T. Yanagisawa, M. (2007). Lessons from sleepy mice narcolepsy-cataplexy and the orexin neuropeptide system. In Narcolepsy and Hypersomnia, ed. C. Bassetti, M. Billiard E. Mignot, New York, NY Informa Healthcare, pp. 257-78. 

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. 

Mood and hedonic value associated with feeding, food intake, foraging, consummatory behaviors, and craving in addiction complex regulation by food entrainable oscillators in the brain and periphery, neuropeptides (including orexins) and biogenic amines. 

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. 

The lateral hypothalamic area has been identified as a feeding centre by studies involving electric stimulation and discrete lesions. Neurons in the lateral hypothalamic area and the neighbouring perifornical area express neuropeptides that stimulate feeding when injected into cerebral ventricles (orexins 1 and 2, melanin-concentrating hormone (MCH)). 

Sakurai, T., Amemiya, A, Ishii, M. el al. (1998). Orexins and orexin receptors a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573-85. 

Figure 11.2 Increases in wakefulness after intracerebroventricular (ICV) or intrahypothalamic administration of ghrelin, neuropeptide Y (NPY), and orexin-A in the first hour of the light period in rats. LH, lateral hypothalamus MPA, medial preoptic area PVN, paraventricular nucleus asterisks denote significant differences from baseline. Orexin data are extracted from Vogel et at, J. Neuroscience Methods, 2002, 118 89-96.

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. 

Orexins are two hypothalamically expressed neuropeptide sequences, the gene for which was described concurrently and independently by two groups using different biochemical and genetic approaches (de Lecea, This volume, de... 

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

Fu L. Y., Acuna-Goycolea C., van den Pol A. N. (2004). Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms tonic depression of the hypothalamic arousal system. J. Neurosci. 

Control of feeding behavior involves peripheral peptides (insulin, ghrelin, leptin) plus several peptides in the CNS (orexins/hypocretins, CCK, galanin, MSH, neuropeptide Y, CRH, cocaine-and-amphetamine-regulated transcript (CART)) [35, 36]. Some of the same peptides are involved in reward systems crucial to drug addiction. Specific receptor blockers are being tested for many of these peptide-receptor systems, with the hope of very selective actins with minimal side effects [35], For example, there are two CCK receptor subtypes, CCK-A and... 

Beuckmann CT, Yanagisawa M (2002) Orexins from neuropeptides to energy homeostasis and sleep/wake regulation. J Mol Med 80 329-342... 

There are dozens of presynaptic receptors for endogenous peptides. This review will focus on receptors for four peptides or peptide families the opioid peptides, neuropeptide Y and related peptides, adrenocorticotropic hormone (corticotropin, ACTH), and the orexins. This choice is representative, since part of the receptors inhibit and part of them facilitate transmitter release moreover, the receptors under consideration are coupled to the major G proteins, namely Gl/(), Gs and Gq (Table 1). 

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