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

Since activation of cannabinoid CB1 receptors inhibits gastrointestinal tra nsit in the mouse, this study analyzed the action of the cannabinoid recept or agonist methanandamide on distension-induced propulsive motility. Perist alsis in luminally perfused segments of the guinea-pig isolated ileum was e licited by a rise of the intraluminal pressure. The pressure threshold at w hich peristaltic contractions were triggered was used to quantify drug effe cts. Methanandamide (0.1-3 mu M) inhibited peristalsis as deduced from a co ncentration-related increase in the peristaltic pressure threshold, an acti on that was prevented by the CB1 receptor antagonist SR141716A (1 mu M) per se, which had no effect on peristalsis. The distension-induced ascending r eflex contraction of the circular muscle was likewise depressed by methanan damide 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 u naltered by suramin (300 mu M), pyridoxal-phosphate-6-azophenyl-2',4'-disul phonic acid (150 mu M) and naloxone (0.5 mu M). It is concluded that methan andamide depresses intestinal peristalsis via activation of CB1 receptors o n enteric neurons, which results in blockade of excitatory motor pathways a nd facilitation of inhibitory pathways operating via apamin-sensitive K+ ch annels and nitric oxide. (C) 1999 Elsevier Science Ltd. All rights reserved .