Document Detail


Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism.
MedLine Citation:
PMID:  24592208     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.
Authors:
Christine Dugovic; Jonathan E Shelton; Sujin Yun; Pascal Bonaventure; Brock T Shireman; Timothy W Lovenberg
Related Documents :
15670628 - Computational characterization of behavioral response of medaka (oryzias latipes) treat...
23314238 - Half-fluence photodynamic therapy in chronic central serous chorioretinopathy.
18241238 - A graph-theory framework for evaluating landscape connectivity and conservation planning.
16151048 - Active vision in parietal and extrastriate cortex.
18948968 - Effects of maintained weight loss on sleep dynamics and neck morphology in severely obe...
7853218 - Topography of saccadic eye movements evoked by microstimulation in rabbit cerebellar ve...
Publication Detail:
Type:  Journal Article     Date:  2014-02-14
Journal Detail:
Title:  Frontiers in neuroscience     Volume:  8     ISSN:  1662-4548     ISO Abbreviation:  Front Neurosci     Publication Date:  2014  
Date Detail:
Created Date:  2014-03-04     Completed Date:  2014-03-04     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  101478481     Medline TA:  Front Neurosci     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  28     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Factors that account for inter-individual variability of lateralization performance revealed by corr...
Next Document:  Anatomical limits on interaural time differences: an ecological perspective.