Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain.

Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid andethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acidamidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limitits analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor ofNAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhib-ited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAAcells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflamma-tion as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effectwas accompanied by elevation of PEA endogenous levels in the paw skin.