title: Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive.
abstract: We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators--fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively--which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego, 30, Genova 16163, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA. Electronic address: kmwagner@ucdavis.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine 92697-4621, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002186:Cannabinoids / Q000627:therapeutic use; D002351:Carrageenan; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D010671:Phenylurea Compounds / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries; D013311:Streptozocin; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D002186:Cannabinoids; D002351:Carrageenan; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; D010671:Phenylurea Compounds; D010880:Piperidines; D054852:Small Molecule Libraries; D013311:Streptozocin; D000099252:Fatty Acid Amide Hydrolases; C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; C552918:URB937
keywords: Acute and chronic pain; Anti-nociception; Epoxidized fatty acid (EpFA); Fatty acid amide hydrolase; Fatty acid ethanolamide (FAE); Soluble epoxide hydrolase