Central Cholinergic Modulation of the Cough Reflex: Suppressive Effects of Donepezil in rabbits

Cough is a purposeful airway defensive reflex, but in chronic cough it no longer provides a clear physiological benefit and markedly impairs patient’s quality of life. Currently available antitussive drugs have limited efficacy and may cause severe side effects. Thus, further research is needed to find reliable treatments. It has been shown that acetylcholine (ACh) downregulates cough via muscarinic ACh receptor (mAChRs) in the rabbit caudal portion of the nucleus tractus solitarii (cNTS), with a major involvement of the M4 receptor subtype. The identification of cholinergic agents modulating ACh depressant effects on coughing could be of considerable interest for the development of novel therapeutic strategies. Here we tested the hypothesis that increasing synaptic ACh levels by inhibiting acetylcholinesterase activity may downregulate the cough reflex. In anesthetized, spontaneously breathing rabbits, we investigated the effect of donepezil, a brain-penetrant, potent and selective acetylcholinesterase inhibitor, on the modulation of the cough reflex induced by mechanical and chemical stimulation of the tracheobronchial tree and on the sneeze reflex. Efferent respiratory and electromyographic activities were recorded from phrenic nerves and abdominal muscles, respectively. Donepezil, either systemically administered (5 mg/kg; subcutaneously) or bilaterally microinjected (5 mM; 30-50 nl) into the cNTS, induced strong depressant effects up to the complete abolition of the mechanically-induced cough, without affecting sneezing. Donepezil also decreased expiratory activity even to complete suppression, while transient increases in respiratory frequency were observed only after local application. These findings support further investigation on donepezil and related centrally acting cholinergic agents as candidate antitussive therapies.