Feature

Maintaining wakefulness: the role of orexin neuropeptides

Professor Takeshi Sakurai,
Department of Molecular Neuroscience
and Integrative Physiology, Faculty of
Medicine, Kanazawa University, Japan.

One of Kanazawa University’s leading professors has spent the last 15 years investigating the role of orexin neuropeptides in the brain. Takeshi Sakurai’s work is furthering understanding of sleep and wakeful states and leading to the development of new therapies for insomnia and narcolepsy¹.

In 1998, during a postdoc at the University of Texas, Sakurai discovered orexin A and orexin B – two neuropeptides in the hypothalamus region of rat brains². His team found that the orexins acted as regulators of feeding behaviour in the animals.

“I discovered orexin while searching for endogenous peptide ligands for orphan G-protein receptors,” explains Sakurai. “Since then, I have been working on the physiological roles of orexin, completing intensive studies of orexin-producing neurons.”

Following on from the initial studies into the role of orexin in feeding behaviour, Sakurai proved that the neuropeptides were responsible for triggering wakefulness in order to search for food. Sakurai found that orexin-deficient mice failed to become active or look for food after a period of fasting^3,4.

“Orexin is a critical factor in maintaining and ensuring the stability of wakefulness in the brain, and they interact with systems that regulate emotion, reward and energy balance in the body,” states Sakurai⁵. “Orexin receptors are expressed by neurons in the regions involved in the regulation of arousal, and orexin peptides basically activate these cells. We have since discovered that sleep disorders such as narcolepsy and insomnia are caused by the under- and over-activation of orexins.”

Takeshi Sakurai first discovered
orexin A and B neuropeptides in 1998,
and since then has studied their
morphology and function with regards
to sleep / wake states in the brain.
His research has led to the develop-
ment of treatment for sleep disorders
such as insomnia.

Sakurai and co-workers at Kanazawa University, together with researchers in the USA, have recently revealed the functions of orexin receptors Ox₁R and Ox₂R⁴. Each of these receptors is now understood to have distinct pathways influencing REM and non-REM sleep patterns, with Ox₂R having the most pivotal role.

“From these findings, pharmaceutical companies have now developed orexin receptor antagonists for insomnia treatment,” explains Sakurai. “Agonists for Ox₂R are sought to create therapies for narcolepsy and other sleep problems. We are planning to investigate the receptors in greater detail in order to shed more light on the mechanisms behind orexin activity.”

Publication and Affiliation

^1. Takeshi Sakurai^a* & Michihiro Mieda. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends in Pharmacological Sciences, 32(8) (2011)
^2. Takeshi Sakurai et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 (1998)
^3. Akihiro Yamanaka et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 32 (2003)
^4. Junko Hara et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30 (2001)
^5. Takeshi Sakurai et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46 (2005)
^6. Michihiro Mieda et al. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. Journal of Neuroscience 31 (17) (2011) doi: 10.10161/j.tips.2011.03.007

a. Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Japan

*corresponding author, e-mail address: tsakurai＠med.kanazawa-u.ac.jp