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

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.