Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo‐oxygenase systems

The anti‐inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo‐oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan‐induced acute paw inflammation and compared with the nonsteroidal anti‐inflammatory drug (NSAID) indomethacin. Palmitoylethanolamide (1, 3, 5, 10 mg kg−1; p.o.) and indomethacin (5 mg kg−1; p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO2−/NO3−), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan‐induced oedema in a dose‐ and time‐dependent manner. This effect was not reversed by the selective CB2 receptor antagonist (N‐[(1S)‐endo‐1,3,3‐trimethylbicyclo[2.2.1]heptan‐2yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)pyrazole‐3 carboxamide) (SR144528), 3 mg kg−1 p.o. On the fourth day after carrageenan injection, COX activity and the level of NO2−/NO3−, eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg−1) and indomethacin markedly reduced these increases. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity. British Journal of Pharmacology (2002) 137, 413–420. doi:10.1038/sj.bjp.0704900