Orexin receptors: Multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders

• Published in: Cellular signalling Vol. 25; no. 12; pp. 2413 - 2423
• Main Authors: Xu, Tian-Rui, Yang, Yang, Ward, Richard, Gao, Linghuan, Liu, Ying
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.12.2013
• Subjects: Addiction; Animals; Cancer; Cancers; Cellular; Control; Disorders; Drug addiction; Energy homeostasis; Feeding and Eating Disorders - drug therapy; Feeding and Eating Disorders - metabolism; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - metabolism; Neuropeptides - metabolism; Orexin Receptor Antagonists; Orexin receptors; Orexin Receptors - agonists; Orexin Receptors - metabolism; Orexins; Peptides; Receptors; Reproduction; Signal Transduction - drug effects; Sleep Wake Disorders - drug therapy; Sleep Wake Disorders - metabolism; Sleep/wakefulness state; Substance-Related Disorders - drug therapy; Substance-Related Disorders - metabolism; DRN; rRPa; RVM; NAc; AC; BST; PKA; PKC; MAPK; OX2R; ITIM; GABA; HPA; GPCR; Smad; 5-HT; RN; HPG; ERK; NSCC; VTA; PLC; CNS; HIF1; OX1R; CREB; NPY; Sleep/wakefulness state; Cancers; OxB; OxA; TGF-β; SN; GH; BMP; Orexins; FAA; ITSM; TMN; Addiction; BAT; pCREB; Orexin receptors; PH; HA; Energy homeostasis; REM; LH; ICV; CB1R; immunoreceptor tyrosine-based inhibitory motif; hypothalamic–pituitary–gonadal; neuropeptide Y; nonselective cationic conductance; orexin A; orexin B; adenylyl cyclase; cAMP-response element binding protein; immunoreceptor tyrosine-based switch motif; extracellular signal regulated kinase; food anticipatory activity; hypothalamic–pituitary–adrenal; tuberomammillary nucleus; gamma-aminobutyric acid; rostral ventromedial medulla; nucleus accumbens; central nervous system; dorsal raphe nucleus; cannabinoid receptor type 1; raphe nuclei; bed nucleus of the stria terminalis; ventral tegmental area; transforming growth factor-β; G protein coupled receptors; drosophila mothers against decapentaplegic protein; orexin receptor type 2; orexin receptor type 1; rostral raphe pallidus; histamine; 5-hydroxytryptamine; lateral hypothalamus; posterior hypothalamus; rapid eye movement; mitogen-activated protein kinase; intracerebroventricular; growth hormone; protein kinase A; protein kinase C; phospholipase C; substantia nigra; bone morphogenetic protein; brown adipose tissue; phosphorylated cAMP response element-binding protein; hypoxia-inducible factor-1
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.07.025

The orexin peptides (orexin A, orexin B) and their receptors (orexin receptor type 1, orexin receptor type 2) are involved in multiple physiological processes such as the regulation of sleep/wakefulness state, energy homeostasis and reward seeking. A result of this has been the development of small-molecule orexin receptor antagonists as novel therapies for the treatment of insomnia and drug addiction. Increased levels of signaling via the orexin peptide/receptor system may protect against obesity, while somewhat unexpectedly, orexins acting at orexin receptors induce dramatic apoptosis resulting in the significant reduction of cell growth in various cancer cell lines. Meanwhile, the orexin peptide/receptor system is also involved in cardiovascular modulation, neuroendocrine and reproduction regulation. This review summarizes the latest developments in deciphering the biology of orexin signaling as well as efforts to manipulate orexin signaling pharmacologically. •The orexin signaling is involved in multiple physiological processes.•Orexins, unexpectedly, induce dramatic apoptosis in various cancer cell lines.•Orexin receptor agonists/antagonists can be used to treat multiple disorders.•The multi-functional property of orexin signaling is a double-edged sword.