Orexin: a key to sleep-wake regulation

Orexin is considered a ‘master controller’ of the sleep wake control system. Orexin both stimulates the wake-promoting system, but also stabilises the switching between wake and sleep. As orexin levels rise in the morning people feel more alert. Then around the time of going to sleep at night, orexin levels fall resulting in people feeling less alert.

In the early 2000s, another important discovery highlighted the importance of orexin in maintaining stable wakefulness. People with the condition narcolepsy with cataplexy were found to have very low numbers of orexin neurones in the lateral hypothalamus and low or absent levels of orexin in the fluid surrounding the brain. This finding suggested that blocking orexin at night could induce sleepiness in people having trouble ‘switching off’, getting to sleep or waking through the night.

What is orexin?

Orexin, also called hypocretin, is a neuropeptide produced by neurones in the lateral hypothalamus that regulates arousal, wakefulness and sleep stability. Orexin was discovered in 1998, simultaneously by 2 different groups of researchers. There are 2 forms of orexin: orexin-A and -B, which bind to the G-protein coupled orexin receptors, OX1 and OX2. Orexin-A binds to both OX1 and OX2 receptors with equal affinity, whereas orexin-B binds mainly to OX2.

What role does orexin play in sleep regulation?

Orexin promotes the activity of the monoaminergic wake-promoting systems, and also stabilises the relationship between sleep and wake. When orexin is present in normal levels, people can generally stay awake without falling asleep. However, when orexin levels are low, the GABA-ergic neurones in the ventrolateral pre-optic nucleus (VLPO) become predominant and people go to sleep. If orexin levels are very low or absent, as can happen in narcolepsy, then not only do people feel sleepy but they can go rapidly in to REM sleep or have features of REM sleep, such as vivid dreams (hypogogic hallucinations) or muscle weakness (cataplexy) whilst awake.

orexin and sleep wake regulation


Sleep-wake regulation is also discussed in review papers such as this one in Neuron in 2010.

For more on the role of orexin in sleep regulation, listen to this interview with Prof Daniel Hoyer.

Blocking orexin to treat insomnia

Given orexin’s role in stimulating wakefulness, the pharmaceutical industry has been working on developing orexin antagonists (blockers) as treatments for insomnia. Suvorexant (brand name Belsomra) is the first of these to be approved for use.

Suvorexant is a highly selective dual orexin receptor antagonist which acts on both the orexin 1 (OX1) and orexin 2 (OX2) receptors.  By binding to the orexin receptor, suvorexant blocks the binding of orexin and suppresses waking drive. The major clinical trials of suvorexant tested doses of 20mg (15mg in over 65 years of age) and 40mg (30mg in over 65s). The dose approved or use in Australia is 20mg (15mg for over 65s). The best study to look at suvorexant effectiveness at this dose is the pooled analysis of phase 3 trials published in the Journal of Clinical Sleep Medicine in 2016. (Herring et al, J Clin Sleep Med 2016; 12(9):1215-1225).

The main findings of these studies were that suvorexant at a dose of 20mg helped people:

  • Get to sleep faster: on night 1 people went to sleep 11 minutes faster compared to placebo. This was 9 minutes at the end of 1 month of treatment.
  • Stay asleep longer: after 1  dose, people stayed asleep for 35 minutes more during the night compared to placebo. After 3 months, this was 23 minutes.
  • Sleep longer overall: on night 1 people sleep overall 45 minutes longer compared to placebo. By 3 months this was 28 minutes.

The most common side effect of suvorexant was feeling more sleepy than expected the following morning. This occurred in 7% of people taking suvorexant compared to 3% of people using a placebo. Put another way, for every 25 people taking suvorexant at a dose of 20mg, 1 would experience morning sleepiness as a consequence of taking suvorexant.

Replacing orexin as a treatment for narcolepsy

As narcolepsy with cataplexy is a disorder of orexin deficiency, the ideal treatment would be orexin replacement. However, this is difficult as the receptor structure hasn’t been well characterised and it is difficult to get the required drugs in to the brain, across the blood-brain barrier. However, recent work published in Nature has been able to work out the structure of the human orexin 2 receptor, and how to bind drugs to it that could then either stimulate or inhibit the receptor. Drugs that stimulate the orexin receptor (agonists), would address all of the symptoms by replacing the effects of missing orexin. From this research, other groups have developed orexin receptor agonists, and are moving on to looking at how to get these drugs in to the brain in the required concentrations.

We hope that in 5-10 years orexin receptor agonists will be ready for clinical trials as treatment for narcolepsy with cataplexy.

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