Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness

J Physiol. 2009 May 1;587(Pt 9):2059-67. doi: 10.1113/jphysiol.2008.168260. Epub 2009 Mar 9.


Recent data from transgenic mice suggest that orexin plays an important role in the ventilatory response to CO(2) during wakefulness. We hypothesized that orexin receptor-1 (OX(1)R) in the retrotrapezoid nucleus (RTN) contributes to chemoreception. In unanaesthetized rats, we measured ventilation using a whole-body plethysmograph, together with EEG and EMG. We dialysed the vehicle and then SB-334867 (OX(1)R antagonist) into the RTN to focally inhibit OX(1)R and studied the effects of both treatments on breathing in air and in 7% CO(2). During wakefulness, SB-334867 caused a 30% reduction of the hyperventilation induced by 7% CO(2) (mean +/- S.E.M., 135 +/- 10 ml (100 g)(-1) min(-1)) compared with vehicle (182 +/- 10 ml (100 g)(-1) min(-1)) (P < 0.01). This effect was due to both decreased tidal volume and breathing frequency. There was a much smaller, though significant, effect in sleep (9% reduction). Neither basal ventilation nor oxygen consumption was affected. The number and duration of apnoeas were similar between control and treatment periods. No effect was observed in a separate group of animals who had the microdialysis probe misplaced (peri-RTN). We conclude that projections of orexin-containing neurons to the RTN contribute, via OX(1)Rs in the region, to the hypercapnic chemoreflex control during wakefulness and to a lesser extent, non-rapid eye movement sleep.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoxazoles / administration & dosage*
  • Hypercapnia / physiopathology
  • Male
  • Naphthyridines
  • Neural Inhibition / drug effects*
  • Orexin Receptors
  • Pulmonary Ventilation / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism*
  • Respiratory Center / drug effects
  • Respiratory Center / physiopathology*
  • Urea / administration & dosage
  • Urea / analogs & derivatives*
  • Wakefulness / drug effects*


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Benzoxazoles
  • Naphthyridines
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Urea