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

Abstract

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% CO(2)) or hypoxic (15 or 10% O(2)) 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 mlxmin(-1)xg(-1)x% CO(2)(-1)) was significantly blunted compared with that in WT mice (0.51 +/- 0.05 mlxmin(-1)xg(-1)x% CO(2)(-1)). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 +/- 0.03 mlxmin(-1).g(-1)x% CO(2)(-1) for orexin-A and 0.32 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1) for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-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 CO(2) sensitivity at least during wake periods in mice.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…The role of orexin in modulating pulmonary changes in response to plasma hypoxia and hypercapnia, however, is less clear. Observations of ventilatory responses to these conditions in orexin peptide knockouts and after central administration of orexin peptides has been mixed; some studies have found an involvement of orexin in mediating increased ventilatory responses to hypercapnia (Deng et al, 2007;Nakamura et al, 2007;Dias et al, 2009Dias et al, , 2010Nattie and Li, 2010), decreased pulmonary activity to hypoxia (Deng et al, 2007;Nakamura et al, 2007), or no detectable response to either condition (Zhang et al, 2005). Conversely, a study of patients with narcolepsy-cataplexy detected attenuated responses to hypoxia but not hypercapnia (Han et al, 2010), which is exactly opposite that found in rodent models.…”

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

“…These warm-sensitive POAH neurons are also CO 2 sensitive (Wright and Boulant, 2007). Likewise, orexinergic neurons in the lateral hypothalamus are involved in feeding, arousal and ventilatory control, and are also CO 2 sensitive (Williams et al, 2007), and orexin-null mice exhibit a substantially blunted HCVR (Deng et al, 2007). Similarly, raphé 5-HT neurons respond to central (Nason and Mason, 2006) and peripheral (Martin-Cora et al, 2000) cooling and augment cold-induced thermogenesis, facilitate respiratory rhythm generation (Pena and Ramirez, 2002) and respiratory motor output (Brandes et al, 2006), and play a major role in ventilatory control during hypercapnia.…”

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

“…This ORX system is critical for maintaining wakefulness (for review, see Sakurai, 2007) and a hyperactive ORX system is linked to: a rodent model of COPD (Liu et al, 2010); clinical COPD with hypercapnic respiratory disorder (Zhu et al, 2011); and anxiety-and panic-vulnerability in rats and humans (Johnson et al, 2010). Furthermore, during wakefulness prepro-ORX knockout mice have blunted respiratory responses to 5-10% hypercarbic gas exposure, and injecting wild-type mice with an ORX1 receptor antagonist attenuates hypercapnic-induced respiratory responses (Deng et al, 2007). The present studies in rats attempted to determine the role that ORX has in the behavioral and cardiovascular responses to an acute 20% CO 2 /normoxic gas challenge (a stimulus where ambient CO 2 concentrations rise and peak just at the 5-min point, then rapidly decreases at offset; Johnson et al, 2005).…”