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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.

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Hot cat sex 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 Hot cat sex 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.

Intwo groups searching for new signaling molecules independently discovered the orexin neuropeptides and their receptors. Sakurai, Yanagisawa, and colleagues 1 Hot cat sex these peptides orexin-A and -B because they were originally thought to promote feeding the term orexin comes from orexisthe Greek word for appetite.

The team led by de Lecea and Sutcliffe 2 named the peptides hypocretin-1 and -2 because they are produced in the hypothalamus and have some similarities to the incretin family of peptides.

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Over the past decade, it has become clear that although the orexin peptides have only a modest influence on feeding and appetite, their effects on arousal and sleep are profound. In fact, narcolepsy, one of the Hot cat sex common causes of sleepiness, is caused by a loss of the orexin-producing neurons, and this has fueled a strong interest in developing orexin antagonists as a novel approach for promoting sleep and treating insomnia. In contrast, orexin antagonists are expected to promote sleep with fewer side effects, and recent, large clinical studies look promising.

In this article, we review the neurobiology of orexin signaling, recent preclinical and clinical studies Hot cat sex orexin antagonists, and potential applications of these compounds for the treatment of insomnia and other disorders.

Orexin-A and -B are derived from the cleavage of prepro-orexin 12. Orexin-A consists of 33 amino acids with two disulfide bridges, and orexin-B is a linear peptide of 28 amino acids that probably forms two alpha helices 3. Each peptide is amidated at the C terminus, and the N terminus of orexin-A is also cyclized with a pyroglutamyl residue.

The peptides are packaged in Hot cat sex core vesicles and most likely synaptically released 2. Little is known about the kinetics of the orexins, but orexin-A seems to induce longer-lasting behavioral effects, perhaps because of the post-translational modifications Hot cat sex4.

The orexin peptides are highly conserved between humans and mice, with identical orexin-A sequences and just two amino acid substitutions in orexin-B 1. Many other vertebrates including zebrafish also produce orexins, but invertebrates seem to lack orexin-like peptides.

The orexin peptides are produced by a cluster of neurons in the hypothalamus that encircles the fornix and extends across the lateral hypothalamus.

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The human brain contains 50,—80, orexin-producing neurons 56and these cells have extensive projections to many brain regions 7. Some of the heaviest projections are to nuclei that regulate arousal and motivation, including the noradrenergic neurons of the locus coeruleus, the histaminergic neurons of the tuberomammillary nucleus TMNthe serotonergic neurons of the raphe nuclei, and the dopaminergic neurons of the ventral tegmental area VTA Figure 1.

The orexin neurons also innervate cholinergic and noncholinergic neurons in the basal forebrain and project directly to the cortex. Through these projections, the orexin system is well positioned to coordinate the activation of many Hot cat sex systems involved in various aspects of arousal.

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