Modulation of the endocannabinoid system by the fatty acid amide hydrolase, monoacylglycerol and diacylglycerol lipase inhibitors as an attractive target for secretory diarrhoea therapy.

Secretory diarrhoea is a leading cause of mortality and morbidity worldwide. Our aim was to characterize the effect of inhibition of selected enzymes involved in the synthesis or degradation of endocannabinoids on electrolyte equilibrium in the mouse colonic tissue. The aim of this study was to evaluate the effects of PF-3845, JZL-184 and RHC-80267, as inhibitors of fatty acid amide hydrolase (FAAH), monoacylglycerol (MAGL) and diacylglycerol lipase (DAGL), respectively on epithelial ion transport in isolated mouse colon stimulated by forskolin (FSK), veratridine (VER) and bethanechol (BET). Next, colonic tissue was co-incubated with selected inhibitors and cannabinoid receptor antagonists: AM 251 and AM 630 (CB₁ and CB₂ antagonists, respectively). We found that PF-3845 induced antisecretory effect in FSK-stimulated colonic tissue (P < 0.01), which was significantly reversed by AM 251 (P < 0.001) and AM 630 (P < 0.01). JZL-184 significantly reduced ΔI_sc (P < 0.05) in FSK-stimulated conditions and co-incubation with AM 630, but not AM 251 reversed this effect when compared to JZL-184 alone (P < 0.05). After addition of PF-3845 and JZL-184 to colon tissue stimulated by VER, we did not observe any significant effect on ΔI_sc. PF-3845, JZL-184 or RHC-80267 were without any statistically significant effect on BET-evoked ion transport when compared to control. Our findings showed that indirect modulation of the endocannabinoid system could be an attractive target for novel effective treatment of secretory diarrhoea, which is devoid of side effects on the central nervous system caused by direct administration of cannabinoid receptor agonists.