Abstract
Airway vagal nerves play a predominant role in the neural control of the airway, and augmented airway vagal activity is known to play important roles in the pathogenesis of some chronic inflammatory airway diseases. Several lines of evidence indicate that dysfunctional central orexinergic system is closely related to the severity of airway diseases, however, whether orexins affect airway vagal activity is unknown. This study investigates whether and how orexin-A regulates the activity of medullary airway vagal preganglionic neurons (AVPNs). The expression of orexin receptor type 1 (OX1R) and type 2 (OX2R) was examined using immunofluorescent staining. The effects of orexin-A on functionally identified inspiratory-activated AVPNs (IA-AVPNs), which are critical in the control of airway smooth muscle, were examined using patch-clamp in medullary slices of neonatal rats. Airway vagal response to injection of orexin-A into the magna cisterna was examined using plethysmography in juvenile rats. The results show that retrogradely labeled AVPNs were immunoreactive to anti-OX1R antibody and anti-OX2R antibody. Orexin-A dose-dependently depolarized IA-AVPNs and increased their firing rate. In synaptically isolated IA-AVPNs, the depolarization induced by orexin-A was blocked partially by OX1R antagonist SB-334867 or OX2R antagonist TCS OX2 29 alone, and completely by co-application of both antagonists. The orexin-A-induced depolarization was also mostly blocked by Na+/Ca2+ exchanger inhibitor KB-R7943. Orexin-A facilitated the glutamatergic, glycinergic and GABAergic inputs to IA-AVPNs, and the facilitation of each type of input was blocked partially by SB-334867 or TCS OX2 29 alone, and completely by co-application of both antagonists. Injection of orexin-A into the magna cisterna of juvenile rats significantly increased the inspiratory and expiratory resistance of the airway and consequently decreased the dynamic compliance of the lungs, all of which were prevented by atropine sulfate or bilateral vagotomy. These results demonstrate that orexin-A excites IA-AVPNs via activation of both OX1R and OX2R, and suggest that increased central synthesis/release of orexins might participate in the pathogenesis of airway diseases via over-activation of AVPNs.
Highlights
The pulmonary branch of the parasympathetic nervous system plays a key role in the neural control of airway function; and dysfunction of this vagal branch has long been suggested to participate in the pathogenesis of some chronic airway diseases such as bronchial asthma and obstructive sleep apnea syndrome (Lutz and Sukowski, 2004; Lewis et al, 2006; Leung, 2009)
While all of the retrogradely labeled airway vagal preganglionic neurons (AVPNs) examined (>100) in the compact portion of the nucleus ambiguus (cNA) showed positive orexin receptor type 1 (OX1R) immunoreactivity, none of them was positively immunoreactive for antiOX2R antibody
Orexin-A caused significant frequency increases in the glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) and GABAergic and glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs), but not in the glutamatergic miniature excitatory postsynaptic currents (mEPSCs) and GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs). These results suggest that the action sites of orexin-A are most likely at the soma and/or dendrites of the neurons presynaptic to IA-AVPNs, while least likely at the terminals of them
Summary
The pulmonary branch of the parasympathetic (vagal) nervous system plays a key role in the neural control of airway function; and dysfunction of this vagal branch has long been suggested to participate in the pathogenesis of some chronic airway diseases such as bronchial asthma and obstructive sleep apnea syndrome (Lutz and Sukowski, 2004; Lewis et al, 2006; Leung, 2009). The airway vagal tone is determined by central airway vagal preganglionic neurons (AVPNs), which project efferent fibers to postganglionic neurons innervating the smooth muscle, submucosal glands and vasculature of the airway (Baker et al, 1986; Undem et al, 1990; Dey et al, 1996; Maize et al, 1998; Hadziefendic and Haxhiu, 1999). The AVPNs within the DMV primarily innervate tracheobronchial secretory glands and vasculature, and activation of these neurons has little effect on airway resistance (Haselton et al, 1992; Kc et al, 2004). It is reasonable to assume that the ‘‘bursting’’ postganglionic neurons are predominately controlled by IA-AVPNs while the ‘‘tonic’’ postganglionic neurons by II-AVPNs. different subpopulations of AVPNs may exert distinct but coordinated actions in controlling airway function, IA-AVPNs in the eNA may be critically important in controlling airway smooth muscle
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