Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy.
BACKGROUND
The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy.


METHODS
In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography.


RESULTS
Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions.


CONCLUSIONS
In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.
Department of Psychiatry and Psychotherapy, Christian Albrecht University, Niemannsweg 147, D-24105 Kiel, Germany. p.baier@zip-kiel.de
P C
PC
Baier
M
M
Hallschmid
M
M
Seeck-Hirschner
S L
SL
Weinhold
S
S
Burkert
N
N
Diessner
R
R
Göder
J B
JB
Aldenhoff
D
D
Hinze-Selch
D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000188:drug therapy*; D009479:Neuropeptides / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000008:administration & dosage*; D000068797:Orexins; D010865:Pilot Projects; D017286:Polysomnography; D012895:Sleep, REM / Q000187:drug effects*; D016896:Treatment Outcome; D014851:Wakefulness / Q000187:drug effects*; D055815:Young Adult
C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins