Respiratory regulation in narcolepsy

Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, cataplexy and intrusive REM sleep. Deficits in endogenous orexins are a major pathogenic component of the disease. This disorder is also associated with the gene marker, HLADQB1*0602. An increased prevalence of sleep apnea in narcolepsy suggested interactions among ventilatory chemosensitivity, narcolepsy-cataplexy, and sleep apnea. Evidence from animal studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist demostrated that orexins are also contributed to respiratory regulation in a vigilance state-dependent manner, as animals with orexins dysregulation have attenuated hypercapnic ventilatory responses predominately in wakefulness, which is consistent with the notion that the activity of orexinergic neurons is higher during wake than sleep periods. Human model of hypocretin deficiency is patients with narcolepsy-cataplexy. In contrast to findings suggested by animal studies, we found significant decrease 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. Unlike in mouse, hypocretin-1 is not a major factor contributing to chemoresponsiveness in human. Species differences may exist.