title: Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness.
abstract: 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.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756-0001, USA.
authors.forename: Mirela Barros
authors.initials: MB
authors.lastname: Dias
authors.forename: Aihua
authors.initials: A
authors.lastname: Li
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Nattie
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage*; D006935:Hypercapnia / Q000503:physiopathology; D008297:Male; D009287:Naphthyridines; D009433:Neural Inhibition / Q000187:drug effects*; D064446:Orexin Receptors; D012123:Pulmonary Ventilation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012125:Respiratory Center / Q000187:drug effects / Q000503:physiopathology*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014851:Wakefulness / Q000187:drug effects*
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea