Excitatory transmission to the circular muscle of the guinea‐pig ileum: evidence for the involvement of cannabinoid CB 1 receptors

1 The effect of cannabinoid drugs has been investigated on cholinergic and non‐adrenergic non‐cholinergic (NANC) contractile responses to the circular smooth muscle of guinea‐pig ileum elicited by electrical field stimulation (EFS). 2 The cannabinoid receptor agonist WIN 55,212‐2 (1–1000 n m ) and the putative endogenous ligand anandamide (0.1–100 μ m ) both produced a concentration‐dependent inhibition of the cholinergic (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 Apamin (30 n m ), a blocker of Ca 2+ ‐activated K + channels, reduced the inhibitory effect of WIN 55,212‐2 on cholinergic, but not NANC, contractile response. N G ‐nitro‐ l ‐arginine methyl ester (100 μ m ), an inhibitor of nitric oxide synthase, or naloxone (1 μ m ), an opioid receptors antagonist, did not modify the inhibitory effect of WIN 55,212‐2 on both cholinergic and NANC contractions. 4 The inhibitory effects of WIN 55,212‐2 and anandamide on both cholinergic and NANC contractile response was competitively antagonized by the cannabinoid CB 1 receptor antagonist SR 141716A (10–1000 n m ). 5 In absence of other drugs, SR 141716A (1–1000 n m ) enhanced cholinergic (1–45% increase) and NANC (2–38% increase) 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 CB 1 receptors produces inhibition of cholinergic and NANC excitatory responses 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 inhibit cholinergic and NANC transmission in the guinea‐pig ileal circular muscle.British Journal of Pharmacology (1998) 124 , 1363–1368; doi: 10.1038/sj.bjp.0701964