Central adenosine A1 receptors inhibit cough via suppression of excitatory glutamatergic and tachykininergic neurotransmission.

Abstract

The adenosine A1 receptor is reported to mediate several excitatory effects in the airways and has inhibitory effects in the CNS. In this study, we investigated the role of peripheral and central A1 receptors in regulating cough and airway obstruction. Drugs were administered to guinea pigs via inhalation or i.c.v. infusion. Following the administration of different drugs, cough was induced by exposing guinea pigs to aerosolized 0.4M citric acid. An automated analyser recorded both cough and airway obstruction simultaneously using whole-body plethysmography. The A1 receptor agonist, cyclopentyladenosine (CPA, administered by inhalation), dose-dependently inhibited cough and also inhibited airway obstruction. Similarly, CPA, administered i.c.v., inhibited both the citric acid-induced cough and airway obstruction; this was prevented by pretreatment with the A1 receptor antagonist DPCPX (i.c.v.). Treatment with DPCPX alone dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was reversed following treatment with either the glutamate GluN1 receptor antagonist D-AP5 or the neurokinin NK1 receptor antagonist FK-888. These findings suggest that activation of either peripheral or central adenosine A1 receptors inhibits citric acid-induced cough and airway obstruction. The data also suggest that tonic activation of central adenosine A1 receptors serves as a negative regulator of cough and airway obstruction, secondary to inhibition of excitatory glutamatergic and tachykininergic neurotransmission.