Opposite role played by GABAA and GABAB receptors in the modulation of peristaltic activity in mouse distal colon

Abstract

We investigated the role of GABA on intestinal motility using as model the murine distal colon. Effects induced by GABA receptors recruitment were examined in whole colonic segments and isolated circular muscle preparations to analyze their influence on peristaltic reflex and on spontaneous and neurally-evoked contractions. Using a modified Trendelenburg set-up, rhythmic peristaltic contractions were evoked by gradual distension of the colonic segments. Spontaneous and neurally-evoked mechanical activity of circular muscle strips were recorded in vitro as changes in isometric tension. GABA, at low concentrations (10–50µM), potentiated peristaltic activity and the neural cholinergic contractions, whilst it, at higher concentrations (500µM–1mM), had inhibitory effects. GABA excitatory effects were mimicked by muscimol, GABAA-receptor agonist, and prevented by bicuculline, GABAA-receptor antagonist, which per se reduced peristaltic activity and the cholinergic contractile responses. Inhibitory effects were mimicked by baclofen, GABAB-receptor agonist, and antagonized by phaclofen, GABAB-receptor antagonist and by hexamethonium, neural nicotinic receptor antagonist. Guanethidine was ineffective on GABA effects. Non-cholinergic responses were not affected by GABA agents. All drugs failed to affect the response to carbachol. Lastly, GABAC receptor agonist/antagonist had any effect on colonic motility. In conclusion, GABA in mouse distal colon is a modulator of peristaltic activity via the regulation of acetylcholine release from cholinergic neurons through interaction with GABAA or GABAB receptors. GABAA receptors are recruited at low GABA concentrations, increasing acetylcholine release and propulsive activity. At high GABA concentrations the activation of GABAB receptors overrides GABAA receptor effects, decreasing acetylcholine release and peristaltic activity.