Targeting the GABA_B receptors for the treatment of gastroesophageal reflux disease and chronic cough

Transient lower esophageal sphincter relaxation (TLESR) is the dominating motor event behind gastroesophageal reflux (GER) and therefore an important factor in gastroesophageal reflux disease (GERD). TLESR is a reflex dependent on the vagus and as such, it shares many similarities with the cough reflex. Moreover, GER is a known cause of chronic cough in some patients, and agents inhibiting both TLESR and cough may be useful antitussives. There is no effective therapy for GERD patients whose symptoms are not fully resolved by proton pump inhibitor (PPI) therapy and marketed antitussives have poor effects in most patients suffering from chronic cough. The observations that GABA type B (GABA_B) receptor agonists reduce TLESR and inhibit cough regardless of stimulus open new inroads to the treatment of PPI-resistant GERD as well as GER-related cough. The present review focuses on these aspects and discusses the findings of GABA_B receptor agonists on TLESR, GER, GERD, and cough in both the preclinical setting, healthy individuals and patients. Special attention is devoted to the role of the vagus in mediating these pharmacological effects.