Orexin‐A and respiration in a rat model of smoke‐induced chronic obstructive pulmonary disease

Abstract

SUMMARY1. Orexins are neuropeptides synthesized in the hypothalamus that regulate many physiological functions, including energy homeostasis, stress responses, sleep ⁄ wake states etc. It is now emerging that orexins may also regulate breathing, but little is known as to how they do this, particularly in chronic obstructive pulmonary disease (COPD). In the present study, we used a rat model of cigarette smoke-induced COPD to investigate orexin-A expression in the hypothalamus and medulla and its effect on respiration.2. Sprague-Dawley rats were exposed to cigarette smoke (1 h twice daily) for 12 weeks. Lung function and pathological changes associated with inflammation and emphysema were determined to confirm the validity of the COPD model.3. Hypothalamic and medullary orexin-A levels, as determined by radioimmunoassay, were higher in smoke-exposed than control rats. Furthermore, the expression of prepro-orexin (PPO) mRNA in the hypothalamus and orexin OX 1 receptor mRNA in the medulla, as determined by real-time quantitative polymerase chain reaction, was higher in smoke-exposed than control rats.4. The number of orexin-A-positive neurons in the hypothalamus and OX 1 and OX 2 receptor-positive neurons in the ventrolateral medulla was higher in smoke-exposed than control rats.5. Microinjection of orexin-A (1 lmol ⁄ L, 0.1 lL) into the pre-Bötzinger complex enhanced phrenic nerve discharge to a greater extent in smoke-exposed compared with control rats (61% vs 36%, respectively).6. The findings of the present study demonstrate that the increased respiratory activity in smoke-exposed rats is due to an increase in orexin-A as well as upregulation of orexin receptors in the ventrolateral medulla.

Orexins and fear: implications for the treatment of anxiety disorders

“…In a human study, orexin A plasma levels were dramatically increased in patients with chronic obstructive pulmonary disease (COPD), a condition associated with hypercapnia and a tenfold increased risk of panic attacks [66]. Consistent with this, chronic exposure to cigarette smoke tripled hypothalamic orexin A expression in a rodent model of COPD [67]. In addition, rat exposure to hypercapnic air increased c-Fos expression in orexin neurons, and promoted anxietylike behavior, which was prevented by systemic injection of SB334867 [68].…”

Plasma orexin-A and ghrelin levels in patients with chronic obstructive pulmonary disease: Interaction with nutritional status and body composition

“…Ghrelin is also an important polypeptide that stimulates food intake (12,13). Orexins play an important role in various physiological events, including the stress response and the sleep/wake cycle (14). In a previous study, orexin-A levels in patients with COPD were reported to be lower than those in the control group.…”

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

“…However, this is not safe because of significant respiratory depression and other peripheral side effects. Recently, COPD was modeled in rats by exposing them to chronic cigarette smoke (1 h, twice/day over 12 weeks) (Liu et al, 2010). By week 12, the COPD rats compared with control rats, had: (1) COPD-associated lung pathology (ie, coalesced alveoli and thickened bronchiolar walls); (2) 4100% increase in hypothalamic and medullary ORX-A protein expression; and (3) heightened phrenic nerve responses to ORX-A injections into the pre-Bötzinger complex.…”

“…Compared with ORX-B, ORX-A binds with a higher affinity to the ORX1 receptor, which is the receptor targeted here (for review, see Sakurai, 2007). 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).…”