EXCITATORY TRANSMISSION TO THE CIRCULAR MUSCLE OF THE GUINEA-PIG ILEUM - EVIDENCE FOR THE INVOLVEMENT OF CANNABINOID CB1 RECEPTORS

1. The effect of cannabinoid drugs has been investigated on cholinergi c and non-adrenergic noncholinergic (NANC) contractile responses to th e circular smooth muscle of guinea-pig ileum elicited by electrical he ld stimulation (EFS). 2 The cannabinoid receptor agonist WIN 55,212-2 (1-1000 nM) and the putative endogenous ligand anandamide (0.1-100 mu M) both produced a concentration-dependent inhibition of the cholinerg ic (9-57% and 1-51% inhibition) and NANC (9-55% and 2-57% inhibition) contractile responses. WIN 55,212-2 and anandamide did not modify the contractions produced by exogenous acetylcholine or substance P. 3 Apa min (30 nM), a blocker of Ca2+-activated K+ channels, reduced the inhi bitory effect of WIN 55,212-2 on cholinergic, but not NANC, contractil e response. N-G-nitro-L-arginine methyl ester (100 mu M), an inhibitor of nitric oxide synthase, or naloxone (1 mu M), an opioid receptors a ntagonist, did not modify the inhibitory effect of WIN 55,212-2 on bot h cholinergic and NANC contractions. 4 The inhibitory effects of WIN 5 5,212-2 and anandamide on both cholinergic and NANC contractile respon se was competitively antagonized by the cannabinoid CBI receptor antag onist SR 141716A (10-1000 nM). 5 In absence of other drugs, SR 141716A (1-1000 nhl) enhanced cholinergic (1-45% increase) and NANC (2-38% in crease) contractile responses elicited by electrical stimulation, but did not modify the contractions produced by acetylcholine or substance P. 6 It is concluded that activation of prejunctional cannabinoid CB1 receptors produces inhibition of cholinergic and NANC excitatory resp onses in the guinea-pig circular muscle. The inhibition of cholinergic (but not NANC) transmission involves activation of apamin-sensitive K + channels. In addition, an endogenous cannabinoid ligand could inhibi t cholinergic and NANC transmission in the guinea-pig ileal circular m uscle.