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Allergic lung inflammation affects central noradrenergic control of cholinergic outflow to the airways in ferrets

Departments of ¹Pediatrics, ²Nutrition, ³Anatomy, and ⁴Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio; and ⁵Department of Physiology and Biophysics, Howard University, Washington, District of Columbia

Submitted 19 October 2006 ; accepted in final form 5 September 2007

Brain stem noradrenergic cell groups mediating autonomic responses to stress project to airway-related vagal preganglionic neurons (AVPNs). In ferrets, their activation produces withdrawal of cholinergic outflow to the airways via release of norepinephrine and activation of _2A-adrenergic receptors (_2A-AR) expressed by AVPNs. In these studies, we examined the effects of allergen exposure of the airway (AE) with ovalbumin on noradrenergic transmission regulating the activity of AVPNs and, consequently, airway smooth muscle tone. Experiments were performed in vehicle control (Con) and AE ferrets. Microperfusion of an _2A-AR agonist (guanabenz) in close proximity to AVPNs elicited more pronounced effects in Con than AE ferrets, including a decrease in unit activity and reflexly evoked responses of putative AVPN neurons with a corresponding decrease in cholinergic outflow to the airways. Although no differences were found in the extent of noradrenergic innervation of the AVPNs, RT-PCR and Western blot studies demonstrated that AE and repeated exposure to antigen significantly reduced expression of _2A-ARs at message and protein levels. These findings indicate that, in an animal model of allergic asthma, sensitization and repeated challenges with a specific allergen diminish central inhibitory noradrenergic modulation of AVPNs, possibly via downregulation of _2A-AR expression by these neurons.

asthma; airway-related vagal preganglionic neurons; unit discharge; _2A-adrenergic receptors; guanabenz; reverse transcriptase-polymerase chain reaction; Western blotting