Narcolepsy, orexins and respiratory regulation

Abstract

Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, cataplexy and intrusive rapid–eye movement sleep. Deficits in endogenous orexins are a major pathogenic component of the disease. This disorder is also associated with the gene marker HLADQB1*0602. Orexins as hypothalamic neuropeptides have multiple physiological functions, and their primary functions are regulation of the sleep–wake cycle and feeding. Evidence from animal studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist at the retrotrapezoid nucleus and medullary raphe in rats demonstrated that orexins also contribute to respiratory regulation in a vigilance state–dependent manner, as animals with orexin dysregulation have attenuated hypercapnic ventilatory responses predominantly in wakefulness. These findings are consistent with the notion that the activity of orexinergic neurons is higher during wake than sleep periods. Orexin neurons seem to be a pivotal link between conscious and unconscious brain functions in animals. The human model of hypocretin deficiency is patients with narcolepsy–cataplexy. In contrast to the findings suggested by animal studies, we found significant decreases in hypoxic responsiveness, but not in hypercapnic responsiveness, in narcoleptics, and further analysis indicated that decreased ventilatory responses to hypoxia in human narcolepsy–cataplexy is in relation to HLA-DQB1*0602 status, not hypocretin deficiency. This is confirmed by the fact that the hypoxic responsiveness was lower in HLA positive versus negative controls. Unlike in mice, hypocretin-1 is not a major factor contributing to depressed hypoxic responses in humans. Species differences may exist.