GABA_BR expressed on vagal afferent neurones inhibit gastric mechanosensitivity in ferret proximal stomach

GABA_B-receptor (GABA_BR)agonists reduce transient lower esophageal sphincter relaxation (TLESR) and reflux episodes through an action on vagal pathways. In this study, we determined whether GABA_BR are expressed on vagal afferent neurones and whether they modulate distension-evoked discharge of vagal afferents in the isolated stomach. Vagal mehanoreceptor activity was recorded following distensions of the isolated ferret proximal stomach before and after perfusion with the GABA_BR-selective agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA). Retrograde labeling and immunohistochemistry were used to identify GABA_BR located on vagal afferent neurones in the nodose ganglia. Vagal afferent fibers responded to isovolumetric gastric distension with an increase in discharge. The GABA_B-receptor agonists baclofen (5 × 10^-5 M) and 3-APPiA (10^-6 to 10^-5 M) but not muscimol (GABA_A-selective agonist: 1.3 × 10^-5 M) significantly decreased afferent distension-response curves. The effect of baclofen (5 × 10^-5 M) was reversed by the GABA_B-receptor antagonist CGP 62349 (10^-5 M). Over 93% of retrogradely labeled gastric vagal afferents in the nodose ganglia expressed immunoreactivity for the GABA_BR. GABA_BR expressed on vagal afferent fibers directly inhibit gastric mechanosensory activity. This is likely a contributing mechanism to the efficacy of GABA_B-receptor agonists in reducing TLESR and reflux episodes in vivo.