Abstract
Insomnia is a common clinical condition portrayed by difficulty in initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning, such as irritability or fatigue during wakefulness. This ailment is one of the most rampant health concerns; however, it represents an everyday struggle to clinicians because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologic treatments. The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminating in hyperarousal.
Current pharmacological treatment for insomnia exists in the form of benzodiazepine receptor agonist drugs (GABA-A receptor). Nonetheless, the use of these hypnotic medications must be carefully monitored for adverse effects and concerns persist regarding their safety and limited efficacy.
The recent advances made in elucidating the processes of sleep/wake regulation have altered the way that insomnia is approached. Current studies have highlighted new targets for drug discovery. One of the most promising ones is the orexin (hypocretin) system. Orexin neuropeptides regulate transitions between wakefulness and sleep by promoting arousal through activation of cholinergic/monoaminergic neural pathways. This has led to a swift development of a novel class of drugs that antagonize the physiological effects of orexin. These pharmacological agents may lead to new therapies for insomnia without the side effect profile of benzodiazepines (e.g., impaired cognition, disturbed arousal, and motor balance difficulties); however, antagonizing the orexin system may produce an entirely new plethora of side effects.
Despite the impending side effect profile of orexin antagonists, these drugs will inevitably supplement or replace conventional BZD receptor agonists for treating insomnia.
In this chapter, we will appraise the role of orexin antagonists for the treatment of insomnia.
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References
Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E (2012) The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 35:1097–1104
Borbély AA, Mattmann P, Loepfe M, Strauch I, Lehmann D (1985) Effect of benzodiazepine hypnotics on all-night sleep EEG spectra. Hum Neurobiol 4:189–194
Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S et al (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13:150–155
Chemelli R, Willie J, Sinton CM (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451
de Lecea L, Kilduff T, Peyron C, Gao X, Foye P, Danielson P et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327
Di Fabio R, Pellacani A, Faedo S, Roth A, Piccoli L, Gerrard P et al (2011) Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders. Bioorg Med Chem Lett 21:5562–5567
Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang X, Sutton SW et al (2009) Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 330:142–151
Equihua AC, De la Herrán-Arita AK, Drucker-Colín R (2013) Orexin receptor antagonists as therapeutic agents for insomnia. Front Pharmacol 4:163
Gaillard JM, Schulz P, Tissot R (2009) Effects of three Benzodiazepines (Nitrazepam, Flunitrazepam and Bromazepam) on sleep of normal subjects, studied with an automatic sleep scoring system. Pharmacopsychiatry 6:207–217
Gozzi A, Turrini G, Piccoli L, Massagrande M, Amantini D, Antolini M et al (2011) Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS ONE 6:e16406
Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K et al (2012) Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 79:2265–2274
Hoever P, Dorffner G, Beneš H, Penzel T, Danker-Hopfe H, Barbanoj MJ et al (2012) Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther 91:975–985
Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T et al (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 98:9965–9970
Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S et al (2010) A key role for orexin in panic anxiety. Nat Med 16:111–115
Jupp B, Krivdic B, Krstew E, Lawrence AJ (2011) The orexin receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain Res 1391:54–59
Kalogiannis M, Hsu E, Willie JT, Chemelli RM, Kisanuki YY, Yanagisawa M et al (2011) Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS ONE 6:e18697
Kummangal BA, Kumar D, Mallick HN (2013) Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep. Behav Brain Res 237:59–62
Lanoir J, Killam EK (1968) Alteration in the sleep-wakefulness patterns by benzodiazepines in the cat. Electroencephalogr Clin Neurophysiol 25:530–542
Lebold TP, Bonaventure P, Shireman BT (2013) Selective orexin receptor antagonists. Bioorg Med Chem Lett 23:4761–4769
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376
Lu BS, Zee PC (2010) Neurobiology of sleep. Clin Chest Med 31:309–318
Mang GM, Dürst T, Bürki H, Imobersteg S, Abramowski D, Schuepbach E et al (2012) The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 35:1625–1635
Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25
Mieda M, Hasegawa E, Kisanuki YY, Sinton CM, Yanagisawa M, Sakurai T (2011) Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci 31:6518–6526
Mieda M, Tsujino N, Sakurai T (2013) Differential roles of orexin receptors in the regulation of sleep/wakefulness. Front Endocrinol (Lausanne) 4:57
Morairty SR, Revel FG, Malherbe P, Moreau J-L, Valladao D, Wettstein JG et al (2012) Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS ONE 7:e39131
Peyron C, Tighe DK, van den Pol A, de Lecea L, Heller HC, Sutcliffe JG et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015
Prober DA, Rihel J, Onah AA, Sung R-J, Schier AF (2006) Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish. J Neurosci 26:13400–13410
Renzulli C, Nash M, Wright M et al (2011) Disposition and metabolism of [14C]SB-649868, an orexin receptor antagonist, in humans. Drug Metab Dispos 39:215–227
Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8:171–181
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585
Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA et al (2001) SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132:1179–1182
Smith RJ, Aston-Jones G (2012) Orexin/hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci 35:798–804
Smith MI, Piper DC, Duxon MS, Upton N (2003) Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat. Neurosci Lett 341:256–258
Steiner MA, Gatfield J, Brisbare-Roch C, Dietrich H, Treiber A, Jenck F et al (2013) Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist. ChemMedChem 8:898–903
Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X et al (2013) Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 36:259–267
Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich MS et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474
White CL, Ishii Y, Mendoza T, Upton N, Stasi LP, Bray GA et al (2005) Effect of a selective OX1R antagonist on food intake and body weight in two strains of rats that differ in susceptibility to dietary-induced obesity. Peptides 26:2331–2338
Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY et al (2003) Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice. Neuron 38:715–730
Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ et al (2011) Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 25:52–61
Zisapel N (2012) Drugs for insomnia. Expert Opin Emerg Drugs 17(3):299–317
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De la Herrán-Arita, A.K., Equihua-Benítez, A.C., Drucker-Colín, R. (2015). Orexin/Hypocretin Antagonists in Insomnia: From Bench to Clinic. In: Guglietta, A. (eds) Drug Treatment of Sleep Disorders. Milestones in Drug Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-11514-6_9
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DOI: https://doi.org/10.1007/978-3-319-11514-6_9
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