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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Hypocretin Antagonists in Insomnia Treatment and Beyond

Author(s): Chad Ruoff, Michelle Cao and Christian Guilleminault

Volume 17, Issue 15, 2011

Page: [1476 - 1482] Pages: 7

DOI: 10.2174/138161211796197089

Price: $65


Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

Keywords: Hypocretin, orexin, insomnia, narcolepsy, cataplexy, sleep, MK-4305, almorexant, magnocellular, appetite, amygdala, tuberomammillary, dynorphin, isoquinolin, histamine, hypercapnic, cognition, morphine

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