An in vitro study of the relationship between GABA receptor function and propulsive motility in the distal colon of the rabbit

The effects of γ-aminobutyric acid (GABA), 3-aminopropane sulphonic acid (3-APS) and baclofen on spontaneous, electrically-induced and propulsive motility were investigated in rabbit distal colon. In unstimulated longitudinal (LMPs) and circular muscle strip preparations (CMPs) 3-APS (10-200 μM) and GABA caused a clear-cut relaxation susceptible to desensitization. Baclofen (10-200 μM) caused relaxation in a minority (30%) of preparations. The 3-APS response was sensitive to tetrodotoxin (TTX; 1 μM), SR 95531 (a novel competitive GABA(A)-receptor antagonist) (10 μM), picrotoxinin (30 μM), and insensitive to hyoscine (1 μM) and to a combination of prazosin (1 μM) and propranolol (1 μM). The baclofen response was antagonized by 5-aminovaleric acid (DAVA, 500 μM), TTX and hyoscine and resistant to GABA(A)-receptor and adrenoceptor blockade. GABA(A)-receptors were therefore associated with non-adrenergic non-cholinergic (NANC) inhibitory nerve activation while GABA(B)-receptors were involved in depression of cholinergic tone of smooth muscle. GABA (10-200 μM) elicited both above mentioned effects. In LMPs, baclofen (10-200 μM) dose-dependently inhibited submaximal responses to both cholinergic and NANC inhibitory nerve stimulation. This effect was resistant to SR 95531 and picrotoxinin and prevented by DAVA and baclofen desensitization. GABA (10-200 μM) mimicked the action of baclofen. GABA inhibitory effects persisted in the presence of GABA(A)-receptor blockade. In segments of distal colon, GABA and baclofen (1-200 μM), but not 3-APS (1-200 μM), dose-dependently decreased the velocity of propulsion of an intraluminally-distended balloon. This effect was antagonized by DAVA and GABA or baclofen desensitization and resistant to SR 95531 and picrotoxinin. These antagonists per se had no effect on propulsion. In preparations in which propulsion was slowed by hyoscine (1 μM), baclofen caused no consistent further depression of propulsive activity. Our results show that GABA(A)- and GABA(B)-receptors are present in rabbit colon. GABA(A)-receptor stimulation activates NANC inhibitory nerves without apparently affecting propulsion. GABA(B)-receptors are associated with a reduction of neural (mainly cholinergic) activity subserving muscular tone and peristalsis and appear to be located on both cholinergic and NANC inhibitory nerves. However, the persisting propulsive activity during suppression of GABA(A)- and GABA(B)-receptor function suggests that GABA in enteric neurones is not crucial for the neural circuitry subserving colonic peristalsis in this species.