EFFECTS OF CANNABINOID RECEPTOR LIGANDS ON ELECTROPHYSIOLOGICAL PROPERTIES OF MYENTERIC NEURONS OF THE GUINEA-PIG ILEUM

1 The effect of cannabinoid receptor agonists was studied in guinea-pi g myenteric neurones in vitro by use of conventional intracellular rec ording techniques. 2 Exposure of myenteric neurones of the S-cell type to the cannabinoid receptor agonists WIN 55,212-2 (100 nM) and CP 55, 940 (100 nM) reversibly and significantly depressed the amplitude of f ast excitatory synaptic potentials (fast e.p.s.ps) by 46% and 37%, res pectively. 3 The depressant effect of WIN 55,212-2 and CP 55,940 on fa st e.p.s.p. amplitude (expressed as the area above the amplitude-time curve (mVs)) was significantly greater than that of the vehicle, Tween 80, which had no detectable effect. 4 The inhibitory effect of WIN 55 ,212-2 appeared to be concentration-dependent over the range 1-100 nM. WIN 55,212-3, its (-)-enantiomer (100 nM), was inactive. 5 The cannab inoid CB1 receptor antagonist, SR141716A (1 mu M), reversed the inhibi tory effects of WIN 55,212-2 on fast e.p.s.ps in 38% of neurones teste d (3/8) and acetylcholine (ACh)-induced depolarizations in 42% of neur ones tested (5/12). 6 When tested on its own, SR141716A (1 mu M) cause d a 40-50% reduction in the amplitude of fast e.p.s.ps (n=9). 7 WIN 55 ,212-2 reversibly depressed the amplitude of the slow e.p.s.p. and, in 2 out of 7 neurones, this effect was reversed by SR141716A (1 mu M). 8 It is concluded that cannabinoid-induced inhibition of fast choliner gic synaptic transmission occurred by reversible activation of both pr esynaptic and postsynaptic CB1 receptors and that slow excitatory syna ptic transmission can also be reversibly depressed by cannabinoids. Fu rthermore, it would seem that subpopulations of myenteric S-neurones a nd their synapsing cholinergic and non-cholinergic, nonadrenergic term inals are not endowed with cannabinoid receptors.