INTRODUCTION
Cough is the commonest presenting symptom in physician consultations, yet effective licensed therapies remain an unmet clinical need (1). Most consultations for cough are likely to be a consequence of coughing associated with viral respiratory infections which typically resolve spontaneously however it is estimated that around 10% of the general population suffer from chronic coughing defined as a persistent cough of more than 8 weeks duration (1).
Gamma aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the nervous system, with GABAB receptors found in the brain, airways and the gastrointestinal tract. Animal studies have demonstrated the presence of peripheral GABAB receptors in the upper airways, the trachea and the lower oesophageal sphincter (2). Pre-clinical studies of central and peripheral GABAB agonists suggest that they are potent antitussive agents (3, 4). Interestingly GABAB agonists i.e. baclofen have also been shown to reduce cough responses to inhaled irritants such as capsaicin (5). It is unclear whether this is a central nervous system (CNS) or peripheral nervous system (PNS) effect and whether this change in experimentally evoked cough responses results in reduction of cough frequency in patients. Human data exits on the use of central GABAB agonists (baclofen) as an antitussive agents (5-8). However, CNS side effects such as drowsiness and even seizures have limited the use of baclofen in clinical practice. Lesogaberan is a novel predominantly peripherally acting GABAB receptor agonist, which is devoid of CNS side effects due to its uptake by GABA transporters (GAT) in the CNS, its effect on the human cough reflex is unknown.
We hypothesized that GABAB receptors were capable of inhibiting cough in both the central and peripheral nervous system, and therefore predicted that both a peripherally acting GABAB receptor agonist (lesogaberan), and a centrally acting GABAB receptor agonist (baclofen) would both significantly inhibit cough responses to inhaled capsaicin compared to matched placebo therapy. We therefore performed a trial in healthy controls comparing the effect of single doses of lesogaberan (120mg MR), with baclofen (40mg) and matched placebos on cough responses to inhaled capsaicin.