title: Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models.
abstract: Fatty acid ethanolamides (FAEs), which include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are endogenous agonists of peroxisome proliferator-activated receptor-α (PPAR-α) and important regulators of the inflammatory response. They are degraded in macrophages by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). Previous studies have shown that pharmacological inhibition of NAAA activity suppresses macrophage activation in vitro and causes marked anti-inflammatory effects in vivo, which is suggestive of a role for NAAA in the control of inflammation. It is still unknown, however, whether NAAA-mediated FAE deactivation might regulate pain signaling. The present study examined the effects of ARN077, a potent and selective NAAA inhibitor recently disclosed by our group, in rodent models of hyperalgesia and allodynia caused by inflammation or nerve damage. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The antinociceptive effects of ARN077 were prevented by the selective PPAR-α antagonist GW6471 and did not occur in PPAR-α-deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the proinflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-α.
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Genova, Italy Department of Pharmacology, University of California, Irvine, CA, USA Department of Biological Chemistry, University of California, Irvine, CA, USA Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.forename: Cataldo
authors.initials: C
authors.lastname: Martucci
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.forename: Mauro
authors.initials: M
authors.lastname: Dionisi
authors.forename: Luisa
authors.initials: L
authors.lastname: Mengatto
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Glauco
authors.initials: G
authors.lastname: Tarozzo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Rosalia
authors.initials: R
authors.lastname: Bertorelli
authors.forename: Angelo
authors.initials: A
authors.lastname: Reggiani
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002056:Burns / Q000188:drug therapy / Q000209:etiology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004983:Ethanolamines; D004988:Ethers, Cyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009829:Oleic Acids / Q000502:physiology*; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D058748:Pain Perception / Q000187:drug effects* / Q000502:physiology; D010169:Palmitic Acids; D011832:Radiation Injuries / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C582820:5-phenylpentyl N-((2S,3R)-2-methyl-4-oxo-oxetan-3-yl)carbamate; D000577:Amides; D000700:Analgesics; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D004988:Ethers, Cyclic; D009829:Oleic Acids; D047493:PPAR alpha; D010169:Palmitic Acids; D011993:Recombinant Fusion Proteins; C488250:oleoylethanolamide; C005958:palmidrol; D002351:Carrageenan; D000581:Amidohydrolases; C575348:N-acylethanolamine-hydrolyzing acid amidase, rat; C582821:NAAA protein, mouse; D013755:Tetradecanoylphorbol Acetate