Yu Sun, Ryan K. Tisdale, Thomas S. Kilduff

Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA

© 2021 The Author(s)
Published by S. Karger AG, Basel

• Chapter 3 graphical abstract

The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.

• Although the hypocretin/orexin system has been implicated in numerous physiological processes, it is most prominently associated with its role in the regulation of arousal states.
• While HCRTR1/OX1R has been implicated in the regulation of reward, motivation, and autonomic processes, HCRTR2/OX2R is most strongly associated with sleep-wake control.
• HCRTR2/OX2R activation promotes wakefulness whereas HCRTR2/OX2R antagonism promotes sleep.
• The regulatory role of the hypocretin/orexin system has made HCRTR1/OX1R and HCRTR2/OX2R attractive therapeutic targets and, as of mid-2021, two dual orexin receptor antagonists (DORAs) have been approved for treatment of disrupted nocturnal sleep.
• Selective HCRTR1/OX1R and HCRTR2/OX2R antagonists (1- and 2-SORAs) have shown potential in preclinical testing for the treatment of drug and food reward, motivation, anxiety, and insomnia.
• Hypocretin/orexin deficiency due to degeneration of the hypocretin/orexin-producing neurons underlies the sleep disorder narcolepsy and hypocretin/orexin replacement therapy through development of small molecule agonists is an active area of research in the treatment of this disorder.

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