Central noradrenergic control of cholinergic outflow to the airways in ovalbumin sensitized ferrets

Previously, we have shown that activation of central noradrenergic pathways elicits inhibition of airway‐related vagal preganglionic neurons (AVPN) and withdrawal of cholinergic outflow to the airways, via release of norepinephrine and activation of α2A‐adrenergic receptors (α2A‐AR) expressed by AVPNs (JAP, 94:1999–2009, 2003). In the present study, we examined the effects of sensitization and airway challenges with a specific antigen (ovalbumin) on central noradrenergic signaling pathways regulating airway smooth muscle tone. Our results show that, in control (CON) ferrets (n=4) the decrease in tracheal tone induced by locus coeruleus stimulation (LCst) was significantly greater than in sensitized (SEN) animals (n=5; p<0.05). However, following LCst, the release of norepinephrine within the region of rostral nucleus ambiguus (rNA), the location of AVPNs, was similar in both CON and SEN ferrets. Furthermore, microinjected guanabenz (GBZ), an α2A‐adrenergic receptor (α2A‐AR) agonist, administered within the rNA region had a pronounced inhibitory effect on AVPN unit discharge in response to lung deflation in CON (n=5 units from 2 animals) versus SEN (n=8 units from 3 animals). At any effective concentration of GBZ in rNA, tracheal tension decreased significantly more in CON (n=5) than in SEN (n=5) ferrets (p<0.05). Our results suggest that in ferrets, sensitization and repeated exposure to a specific antigen, diminishes the central inhibitory effects of noradrenergic pathways, probably via downregulation of α2A‐AR expressed by AVPNs. Supported by NIH HL grant 56470.