Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: Comparison to baclofen and other GABAB receptor-selective agonists

Abstract

BackgroundGastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough.MethodsWe have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid.ResultsLesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate.ConclusionsTogether, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects.

Antitussive Drugs—Past, Present, and Future

“…Baclofen, an agonist at the GABA B receptor, has been shown to inhibit capsaicininduced cough in guinea pigs as well as mechanically stimulated cough in cats in a dose-dependent manner (Bolser et al, 1993). The antitussive effect of baclofen occurs through a central site of action, whereas the GABA B agonists 3-APPi (3-amino-propylphophine) and lesogaberan have been demonstrated to inhibit cough through a peripheral site of action (Bolser et al, 1994;Canning et al, 2012). More recently, microinjections of baclofen into the caudal ventral respiratory group region of pentobarbital-anesthetized, spontaneously breathing rabbits were shown to inhibit mechanically stimulated cough (Mutolo et al, 2010).…”

NMDA and GABA receptors as potential targets in cough hypersensitivity syndrome

“…Direct inhibitory effects of GABA B receptor agonists on the excitability of vagal afferent nerves in the oesophagus and stomach have been reported [103][104][105]. Interestingly, lesogaberan inhibited inhaled citric acid induced cough in the conscious normal guinea-pig [90], suggesting that this effect may be derived from activation of GABA B receptors perhaps in vagal C-fibres where they have been reported [106,107], and also including effects on vagal afferent nerves in the oesophagus.…”

“…A specific receptor antagonist for GABA B receptors, SCH 50911, inhibited the antitussive effects of baclofen in the cat and guinea pig [87]. While this antitussive effect of baclofen is most likely to occur through a central site of action [88,89], other GABA B agonists, 3-APPi (3-amino-propylphophine) and lesogaberan, have been shown to inhibit cough via a peripheral site of action [88,90]. Baclofen when administered not only into the caudal ventral respiratory group but also into caudal aspect of the nucleus tractus solitarius of pentobarbital-anesthetized, spontaneously breathing rabbits inhibited mechanically stimulated cough [91,92], confirming a central mode of action for baclofen.…”

Chronic cough

“…Canning et al recently evaluated the effect of lesogaberan, a GABA b receptor agonist, in guinea pigs with citric acid induced cough. 22 They reported that both lesogaberan and baclofen reduced coughing in a dose dependant fashion, but lesogaberan did not affect the respiratory rate. In humans, Xu et al recently reported a small case series of 3 patients with chronic cough who responded to baclofen.…”