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Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice

Departments of ¹Molecular and Integrative Physiology and ²Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba-city, Chiba, Japan; ³Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁴Exploratory Research for Advance Technology Yanagisawa Orphan Project, Japan Science and Technology Corporation, Tokyo, Japan

Submitted 16 January 2007 ; accepted in final form 18 August 2007

We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO₂) or hypoxic (15 or 10% O₂) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX- KO mice (0.22 ± 0.03 ml·min^–1·g^–1·% CO₂^–1) was significantly blunted compared with that in WT mice (0.51 ± 0.05 ml·min^–1·g^–1·% CO₂^–1). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 ± 0.03 ml·min^–1·g^–1·% CO₂^–1 for orexin-A and 0.32 ± 0.04 ml·min^–1·g^–1·% CO₂^–1 for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 ± 0.04 ml·min^–1·g^–1·% CO₂^–1). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO₂ sensitivity at least during wake periods in mice.

breathing control; chemostimulation; hypothalamus; orexin receptor antagonist; respiration

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