Orexin receptors: pharmacology and therapeutic opportunities

Abstract

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has generated considerable interest in developing small-molecule orexin receptor antagonists as a novel therapy for the treatment of insomnia. Orexin antagonists, especially those that block OX2 or both OX1 and OX2 receptors, clearly promote sleep in animals, and clinical results are encouraging: Several compounds are in Phase III trials. As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications.

Figure 1

The orexin system helps integrate motivating signals into arousal responses. This schematic summarizes putative pathways through which signals related to sleep, stress, motivation, and hunger activate the orexin neurons to drive various aspects of arousal. Circadian timing signals that arise in the suprachiasmatic nucleus (SCN) are probably relayed through the dorsomedial nucleus of the hypothalamus (DMH). Many input signals are neurally mediated, but the orexin neurons may also respond to humoral signals associated with hunger such as ghrelin or low glucose.

Figure 2

Orexin signaling mechanisms. Orexin-A signals through both OX1R and OX2R, whereas orexin-B signals mainly through OX2R. Intracellular cascades mediated by G proteins increase intracellular calcium and activate the sodium/calcium exchanger, which depolarizes target neurons. These cascades also inactivate G protein–regulated inward rectifier (GIRK) channels. Increased expression of N-methyl-D-aspartate (NMDA) receptors on the cell surface produces long-lasting increases in neuronal excitability.

Figure 3

Average amounts of rapid eye movement (REM) sleep in control and narcoleptic subjects on continuous bed rest for 24 h. Recordings were begun between 7 and 8 AM, and subjects were allowed to sleep ad lib (n = 10 in each group). Adapted from Reference (methods described in Reference 150).