Role of Hypocretins/Orexins in Narcolepsy

Hello friends!!

This is the first of the four-post series on Narcolepsy.

So let's start. The hypocretins were thought in the past to regulate feeding behaviour and energy metabolism, the word “orexin” is derived from the Greek word for appetite. But later through animal experimentation it was found that in mice, inactivation of two hypocretin receptors reproduces Narcolepsy.

First of all, let us learn that monoaminergic neuronal projections from Tuberomammilary nucleus(histaminergic), Locus Ceruleus(noradrenergic) and the Raphe nucleus(serotonergic) inhibit the Ventrolateral Preoptic Nucleus(VLPO) of hypothalamus.

To put it simply, the transition between sleep and waking is determined by the state of activity of the VLPO. Now imagine a see-saw, on one side we have all these nuclei wanting the person to wake up and on the other side we have VLPO forcing the person to sleep. Whoever gets heavier, metaphorically speaking, chooses the person’s state. 

So what’s the role of orexin/hypocretin ? We can say that it enables a smooth transition between wakefulness to sleep by reinforcing the monoaminergic firing from those three nuclei; hence it indirectly inhibits the VLPO. Hence if we remove orexin from the picture, the person will fall asleep immediately without being able to control; and roughly this is what occurs in Narcolepsy. 

That's all. Do go through the subsequent posts in this series.

Clinical features of Narcolepsy
Diagnosis of Narcolepsy
Treatment of Narcolepsy

-VM