Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice

1. We have studied the effect of palmitoylethanolamide (PEA, 2.5-30 mg kg ^-1, i.p.) on upper gastrointestinal transit in control mice and in mice with chronic intestinal inflammation induced by croton oil. 2. PEA significantly and dose-dependently decreased intestinal transit. The inhibitory effect of PEA (10 mg kg ^-1) was not modified by the cannabinoid CB ₁ receptor antagonist SR141716A (0.3 mg kg ^-1, i.p.), the cannabinoid CB ₂ receptor antagonist SR144528 (1 mg kg ^-1, i.p.), N ^G-nitro-L-arginine methyl ester (L-NAME, 25 mg kg ^-1, i.p.), yohimbine (1 mg kg ^-1, i.p.), naloxone (2 mg kg ^-1, i.p.) or hexamethonium (1 mg kg ^-1, i.p.). 3. PEA levels were significantly decreased in the small intestine of croton oil-treated mice. In these animals, PEA also inhibited motility and this effect was not counteracted by SR141716A (0.3 mg kg ^-1), or SR144528 (1 mg kg ^-1). 4. Pre-treatment of mice with the amidase inhibitor phenylmethyl sulphonil fluoride (PMSF, 30 mg kg ^-1, i.p.) did not modify the inhibitory effect of PEA, either in control or in mice with inflammation. 5. It is concluded that PEA inhibits intestinal motility with a peripheral mechanism independent from cannabinoid receptor activation. The decreased levels of PEA in croton oil-treated might contribute, at least in part, to the exaggerated transit observed during chronic intestinal inflammation.