Hypocretin (also called orexin) is the hypothalamic neuropeptide that is the primary regulator of the wakefulness — it is produced by the hypocretin neurons in the lateral hypothalamus, and it regulates the sleep-wake transitions, the arousal, the motivation, and the reward processing through its actions on the hypocretin receptors (OX1R and OX2R) in the hypothalamus, the brainstem, and the forebrain. The hypocretin system is the master regulator of the wakefulness — it is activated during the wakefulness by the sensory inputs, the stress signals, and the reward stimuli, and it is inhibited during the sleep by the GABAergic and the galaninergic inputs from the ventrolateral preoptic area (VLPO) and the median preoptic nucleus (MnPN). The hypocretin neurons are uniquely sensitive to the metabolic and the inflammatory signals — they are activated by the low glucose, by the ghrelin, and by the inflammatory cytokines, and they are inhibited by the high glucose, by the leptin, and by the serotonergic and the noradrenergic inputs from the brainstem. This metabolic sensitivity of the hypocretin system makes it one of the most important and most integrative systems for the regulation of the sleep-wake cycle, the energy homeostasis, and the arousal — and it explains why the hypocretin deficiency is associated not only with the narcolepsy but also with the obesity, the metabolic syndrome, and the depression. Without adequate hypocretin and wakefulness regulation, the sleep-wake transitions are dysregulated, the excessive daytime sleepiness develops, and the REM sleep is dysregulated — the hallmark of the hypocretin deficiency and of the narcolepsy type 1 (which is caused by the autoimmune destruction of the hypocretin neurons in the lateral hypothalamus).
Hypocretin and the Narcolepsy
Hypocretin supports the wakefulness primarily through the activation of the OX2R receptors in the tuberomammillary nucleus (TMN) and in the basal forebrain — these receptors are the primary targets of the hypocretin in the brain, and their activation promotes the neuronal firing, the histamine release, and the cortical arousal that are the hallmarks of the wakefulness. The OX1R receptors in the locus coeruleus and in the laterodorsal tegmental nucleus are also activated by the hypocretin, and this activation promotes the norepinephrine release and the REM sleep suppression (which is one of the most important functions of the hypocretin system — the hypocretin neurons are active during the wakefulness and are silent during the REM sleep, and this pattern of activity is essential for the normal sleep architecture and for the prevention of the REM sleep intrusion into the wakefulness). The hypocretin deficiency in the narcolepsy type 1 is caused by the autoimmune destruction of the hypocretin neurons — the immune system produces the autoantibodies against the hypocretin neurons, and these autoantibodies destroy the neurons, leading to the severe and irreversible loss of the hypocretin (to less than 10% of the normal levels). This loss of the hypocretin leads to the intrusion of the REM sleep into the wakefulness — producing the cataplexy, the sleep paralysis, the hypnagogic hallucinations, and the excessive daytime sleepiness that are the hallmark of the narcolepsy type 1.
The clinical importance of the hypocretin for the sleep-wake regulation is underscored by the observation that the hypocretin replacement (through the administration of the hypocretin or of the hypocretin receptor agonists) is the most effective treatment for the narcolepsy type 1 and for the excessive daytime sleepiness. The current treatments for the narcolepsy (modafinil, pitolisant, solriamfetol, sodium oxybate) are all indirect stimulants of the hypocretin system or of the monoaminergic systems that are downstream of the hypocretin — and they are all less effective than the direct hypocretin receptor activation would be. The development of the hypocretin receptor agonists (such as the danapine and the selondate) is therefore one of the most promising areas of the sleep medicine, and these compounds are expected to be the most effective and most specific treatments for the narcolepsy and for the other disorders of the excessive daytime sleepiness.
Practical Application
For general hypocretin support for the wakefulness and for the sleep-wake regulation, the evidence-based approach is to support the hypocretin system through the lifestyle and the nutritional interventions that promote the hypocretin neuron health and that enhance the hypocretin receptor sensitivity. The hypocretin neurons are sensitive to the metabolic signals (glucose, ghrelin, leptin), to the inflammatory signals (cytokines, CRP), and to the neurotransmitter signals (serotonin, norepinephrine, histamine) — and the optimisation of these signals through the diet, the exercise, the sleep hygiene, and the stress management is the most effective way to support the hypocretin system and to promote the wakefulness. The hypocretin system is activated by the fasting, by the low-carbohydrate diets, by the intense exercise, and by the cold exposure — and it is inhibited by the high-carbohydrate meals, by the sedentary lifestyle, by the chronic stress, and by the obesity. For comprehensive hypocretin and wakefulness support, the lifestyle approach pairs well with the caffeine (which is the most widely used and most effective stimulant of the hypocretin system — it works by blocking the adenosine receptors, which disinhibits the hypocretin neurons and promotes the wakefulness), with the modafinil (which is the most effective prescription stimulant for the hypocretin system and which is used for the treatment of the narcolepsy and of the other disorders of the excessive daytime sleepiness — it works by increasing the histamine release and by enhancing the activity of the hypocretin system), with the vitamin D (which is a regulator of the immune system and which may protect the hypocretin neurons from the autoimmune destruction — the vitamin D deficiency is associated with an increased risk of the narcolepsy and with the reduced hypocretin levels), and with the omega-3 fatty acids (which are regulators of the membrane fluidity and of the neurotransmitter release and which may enhance the hypocretin receptor sensitivity and the hypocretin neuron function).
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