Cannabinoid 1 (CB 1 ) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon

1 The effects of cannabinoid subtype 1 (CB 1 ) receptor activation were determined on smooth muscle, inhibitory and excitatory motorneuronal function in strips of human colonic longitudinal muscle (LM) and circular muscle (CM) in vitro . 2 Electrical field stimulation (EFS; 0.5–20 Hz, 50 V) evoked a relaxation in LM and CM precontracted with a neurokinin‐2 (NK‐2) selective receptor agonist ( β ‐ala 8 ‐neurokinin A; 10 −6   M ) in the presence of atropine (10 −6   M ); this was unaltered following pretreatment with the CB 1 ‐receptor selective agonist arachidonyl‐2‐chloroethylamide (ACEA; 10 −6   M ). 3 In the presence of nitric oxide synthase blockade with N ‐nitro‐ L ‐arginine (10 −4   M ), EFS evoked a frequency‐dependent ‘on‐contraction’ during stimulation and an ‘off‐contraction’ following stimulus cessation. On‐contractions were significantly inhibited in CM strips by pretreatment with ACEA (10 −6   M ). These inhibitory effects were reversed in the presence of the CB 1 receptor‐selective antagonist N‐ (piperidine‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1 H‐ pyrazole‐3‐carboxamide (10 −7   M ). 4 ACEA did not alter LM or CM contractile responses to acetylcholine or NK‐2 receptor‐evoked contraction. 5 Immunohistochemical studies revealed a colocalisation of CB 1 receptors to cholinergic neurones in the human colon based on colabelling with choline acetyltransferase, in addition to CB 1 receptor labelling in unidentified structures in the CM. 6 In conclusion, activation of CB 1 receptors coupled to cholinergic motorneurones selectively and reversibly inhibits excitatory nerve transmission in colonic human colonic CM. These results provide evidence of a direct role for cannabinoids in the modulation of motor activity in the human colon by coupling to cholinergic motorneurones.British Journal of Pharmacology (2006) 148 , 191–199. doi: 10.1038/sj.bjp.0706710