Intranasal orexin A (hypocretin-1) restores the key REM-sleep abnormalities in human narcolepsy with cataplexy

Narcolepsy with cataplexy is a sleep-wake disorder characterized by REM-sleep disinhibition. The underlying pathology is a deficiency of the neuropeptide orexin A (hypocretin 1). Orexin A is essentially involved in sleep regulation and its substitution restores abnormalities in narcolepsy animal models. We therefore hypothesized that orexin A restores REM-sleep abnormalities in human narcolepsy with cataplexy. Individuals with narcolepsy/cataplexy (n=7) participated in the study. In order to deliver orexin A to the central nervous system we made use of the well-established intranasal administration of neuropeptides. In a double-blind, randomized, cross-over design we applied orexin A or placebo intranasally at 22:00h and performed then a standard polysomnography. Intranasal administration of orexin A to individuals with narcolepsy significantly reduced the rate of individuals starting sleep with sleep onset REM sleep (placebo: 71%, orexin A: 42%; Chi-Square: p<0.0001), REM sleep quantity (placebo: 86.9±11.2min; orexin A: 57.9±8.5min, p=0.041) and REM density (placebo: 7.6±1.3%; orexin A: 5.3±0.7%; p=0.042). Our results clearly demonstrate that intranasal orexin A normalizes the key features of REM sleep disinhibition in the human orexin A deficiency disorder narcolepsy. Thus, the intranasal administration of orexin A provides a new tool for further research to better understand sleep regulation and even might open up an avenue towards innovative, causal treatments.