History of Orexin Research

Abstract

Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are hypothalamic neuropeptides that were discovered as endogenous cognate ligands for two orphan G-protein coupled receptors in 1998. Initially, these peptides were reported as regulators of feeding behavior (Sakurai et al. in Cell 92:573–585, 1998). Thereafter, several studies suggested that orexin deficiency causes narcolepsy in several mammalian species including humans, highlighting roles of this hypothalamic neuropeptide in the regulation of sleep and wakefulness (Sakurai in Nat Rev Neurosci 8:171–181, 2007). Studies of efferent and afferent systems of orexin-producing neurons have revealed that orexin neurons has close interactions with systems that regulate emotion, energy homeostasis, the reward system, and arousal (Boutrel et al. in Proc Natl Acad Sci USA 102:19168–19173, 2005; Yamanaka et al. in Neuron 38:701–713, 2003a; Akiyama et al. in Eur J Neurosci 20:3054–3062, 2004; Mieda et al. in J Neurosci 24:10493–10501, 2004; Sakurai et al. in Neuron 46:297–308, 2005; Yoshida et al. in J Comp Neurol 494:845–861, 2006; Harris et al. in Nature 437:556–559, 2005; Narita et al. in J Neurosci 26:398–405, 2006). Subsequent studies suggested that emotionally salient cues and contexts excite orexin neurons to promote arousal, and to support behavior. This system seems to be important to maintain the vigilance and arousal during doing various motivated and adaptive behaviors. Recently, suvorexant, a dual orexin receptor antagonist, has become clinically available for treatment of insomnia. In this chapter, I will overview the history of orexin research, highlighting some of the physiological roles of orexins.