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

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Blackwell Science Inc

RESUMO

Recent data from transgenic mice suggest that orexin plays an important role in the ventilatory response to CO2 during wakefulness. We hypothesized that orexin receptor-1 (OX1R) 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 (OX1R antagonist) into the RTN to focally inhibit OX1R and studied the effects of both treatments on breathing in air and in 7% CO2. During wakefulness, SB-334867 caused a 30% reduction of the hyperventilation induced by 7% CO2 (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 OX1Rs in the region, to the hypercapnic chemoreflex control during wakefulness and to a lesser extent, non-rapid eye movement sleep.

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