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.