Effect of centrally and peripherally acting GABA_B agonism on the healthy human cough reflex

Background: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABA_B receptors in both the peripheral and central nervous systems inhibit cough. Objective: To compare the effect of central and peripherally acting GABA_B agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. Methods: We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). Results: Fifteen participants enrolled onto the study (median age 29 (IQR 25–44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1–17.9) vs. 11.8coughs (8.8–15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 μM (95%CI 24.4–91.7) vs 37.6 μM (95%CI 19.2–73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1–15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 μM (95%CI 37.2–151.8), p = 0.002). Conclusion: This data suggests the anti-tussive actions of GABA_B agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.