Allergic lung inflammation affects central noradrenergic control of cholinergic outflow to the airways in ferrets.
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 alpha(2A)-adrenergic receptors (alpha(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 alpha(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 alpha(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 alpha(2A)-AR expression by these neurons.
Wilson
Christopher G
CG
Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106-6010, USA. cgwilson@case.edu
Akhter
Shamima
S
Mayer
Catherine A
CA
Kc
Prabha
P
Balan
Kannan V
KV
Ernsberger
Paul
P
Haxhiu
Musa A
MA
D000200:Action Potentials; D000320:Adrenergic Fibers / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016084:Bronchoconstriction; D004195:Disease Models, Animal; D015536:Down-Regulation; D005289:Ferrets; D006143:Guanabenz / Q000008:administration & dosage; D008297:Male; D009433:Neural Inhibition; D009638:Norepinephrine / Q000378:metabolism*; D010047:Ovalbumin; D012333:RNA, Messenger / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D012107:Research Design; D012137:Respiratory System / Q000294:innervation* / Q000503:physiopathology; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
D000316:Adrenergic alpha-Agonists; D000485:Allergens; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D010047:Ovalbumin; D006143:Guanabenz; D009638:Norepinephrine