Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats.
OBJECTIVE
Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism.


METHODS
The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored.


RESULTS
UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals.


CONCLUSIONS
In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth.
Sleep-Wake Disorders Unit, Soroka University Medical Center and Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Ariel
A
Tarasiuk
Sleep-Wake Disorders Unit, Soroka University Medical Center and Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel ; Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Avishag
A
Levi
Sleep-Wake Disorders Unit, Soroka University Medical Center and Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel ; Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Nilly
N
Berdugo-Boura
Sleep-Wake Disorders Unit, Soroka University Medical Center and Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel ; Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Ari
A
Yahalom
Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Yael
Y
Segev
D000081:Acetamides / Q000494:pharmacology; D000402:Airway Obstruction / Q000503:physiopathology*; D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D003345:Corticosterone / Q000032:analysis; D004435:Eating; D004734:Energy Metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D020738:Leptin / Q000097:blood; D008124:Locomotion; D008297:Male; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D012894:Sleep Stages / Q000502:physiology; D050507:Subcutaneous Fat, Abdominal / Q000187:drug effects; D014851:Wakefulness / Q000502:physiology
D000081:Acetamides; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D020738:Leptin; D009479:Neuropeptides; D000068797:Orexins; C519150:almorexant; D003345:Corticosterone
orexin; rat; sleep; upper airway loading