Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice

Abstract

Exogenous administration of orexin can promote wakefulness and respiration. Here we examined whether intrinsic orexin participates in the control of breathing in a vigilance state-dependent manner. Ventilation was recorded together with electroencephalography and electromyography for 6 h during the daytime in prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates. Respiratory parameters were separately determined during quiet wakefulness (QW), slow-wave sleep (SWS), or rapid eye movement (REM) sleep. Basal ventilation was normal in ORX-KO, irrespective of vigilance states. The hypercapnic ventilatory response during QW in ORX-KO (0.19 +/- 0.01 ml.min(-1).g(-1).%CO(2)(-1)) was significantly smaller than that in WT mice (0.38 +/- 0.04 ml.min(-1).g(-1).%CO(2)(-1)), whereas the responses during SWS and REM in ORX-KO were comparable to those in WT mice. Hypoxic responses during wake and sleep periods were not different between the genotypes. Spontaneous but not postsigh sleep apneas were more frequent in ORX-KO than in WT littermates during both SWS and REM sleep. Our findings suggest that orexin plays a crucial role both in CO(2) sensitivity during wakefulness and in preserving ventilation stability during sleep.

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.…”

Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System

“…Acidification increased neural excitability, whereas alkalinization depressed it (Williams et al, 2007). Because orexin affects respiratory function, this mechanism might play an important role on the regulation of respiration (Nakamura et al, 2007).…”

Neural Control of Respiration by the Retrotrapezoid Nucleus.

“…We also confirm that hypercapnia does not change f R during REM sleep (Berthon-Jones & Sullivan, 1984;Horner et al, 2002;Nakamura et al, 2007). By contrast, hypercapnia reportedly produces comparable increases in diaphragmatic EMG and V T across wake, non-REM and REM sleep states (Haxhiu et al, 1987;Horner et al, 2002;Nakamura et al, 2007). Consistent with these observations, a given increment of FiCO 2 produced a similar V T increase during wake, non-REM sleep and REM sleep in our experiments.…”

“…For example, although the respiratory chemoreflexes still operate during REM sleep, the breathing frequency (f R ) is typically unaffected by hypoxia or hypercapnia (Coote, 1982;Berthon-Jones & Sullivan, 1984;Horner et al, 2002;Lovering et al, 2003;Nakamura et al, 2007). Also, in conscious cats ventilated to apnea during non-REM sleep, diaphragmatic EMG reemerges during REM sleep (Orem et al, 2005).…”