Modulation of peristalsis by cannabinoid CB1 ligands in the isolated guinea-pig ileum

1 The effect of cannabinoid drugs on peristalsis in the guinea-pig ileum wa s studied. Peristalsis was induced by delivering fluid into the oral end of an isolated intestinal segment. Longitudinal muscle reflex contraction, th reshold pressure and threshold volume to trigger peristalsis, compliance of the intestinal wall during the preparatory phase (a reflection of the resi stance of the wall to distension) and maximal ejection pressure during the emptying phase of peristalsis were measured. 2 The cannabinoid agonists WIN 55,212-2 (0.3-300 nM) and CP55,940 (0.3-300 nM) significantly decreased longitudinal muscle reflex contraction, complia nce and maximal ejection pressure, while increased threshold pressure and v olume to elicit peristalsis. These effects were net: modified by the opioid antagonist naloxone (1 mu M) and by the alpha-adrenoceptor antagonist phen tolamine (1 mu M). 3 The inhibitory effect of both WIN 55,212-2 and CP55,940 on intestinal per istalsis was antagonized by the cannabinoid CB1 receptor antagonist SR14171 6A (0.1 mu M), but not by the cannabinoid CB2 receptor antagonist SR144528 (0.1 mu M). 4 In absence of other drugs, the CB1 receptor antagonists SR141716A (0.01-1 mu M) and AM281 (0.01-1 mu M) slightly (approximatively 20%) but significa ntly increased maximal ejection pressure during the empty phase of peristal sis without modifying longitudinal muscle reflex contraction, threshold pre ssure, threshold volume to trigger peristalsis and compliance. 5 It is concluded that activation of CB1 receptors reduces peristalsis effi ciency in the isolated guinea-pig, and that the emptying phase of peristals is could be tonically inhibited by the endogenous cannabinoid system.