Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways

Since activation of cannabinoid CB1 receptors inhibits gastrointestinal transit in the mouse, this study analyzed the action of the cannabinoid receptor agonist methanandamide on distension-induced propulsive motility. Peristalsis in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects. Methanandamide (0.1-3 mu M) inhibited peristalsis as deduced from a concentration-related increase in the peristaltic pressure threshold, an action that was prevented by the CB1 receptor antagonist SR141716A (1 mu M) per se, which had no effect on peristalsis. The distension-induced ascending reflex contraction of the circular muscle was likewise depressed by methanandamide in a SR141716A-sensitive manner, whereas indomethacin-induced phasic contractions of the circular muscle were left unchanged by methanandamide. The anti-peristaltic action of methanandamide was inhibited by apamin (0.5 mu M), attenuated by N-nitro-L-arginine methyl ester (300 mu M) and left unaltered by suramin (300 mu M), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (150 mu M) and naloxone (0.5 mu M). It is concluded that methanandamide depresses intestinal peristalsis via activation of CB1 receptors on enteric neurons, which results in blockade of excitatory motor pathways and facilitation of inhibitory pathways operating via apamin-sensitive K+ channels and nitric oxide. (C) 1999 Elsevier Science Ltd. All rights reserved.