Papers of the Week

N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiological actions of palmitoylethanolamide (PEA), an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-α. We have previously reported that the compound ARN19702 ((2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone) is an orally active, reversible NAAA inhibitor (median inhibitory concentration, IC, on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hypersensitivity caused by intraplantar carrageenan injection, paw incision or the sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of sub-acute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place-preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. We evaluated the pharmacological profile of the orally bioavailable NAAA inhibitor ARN19702 in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. We conclude that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. Our findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain, and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential.