title: Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: a role for endogenous fatty-acid ethanolamides?
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty-acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. It has been suggested that the mechanisms of action of NSAIDs could be due to inhibition of cyclooxygenase (COX) and also to an increase in endocannabinoid concentrations. In a previous study we have demonstrated that the local analgesic interaction between anandamide and ibuprofen (a non-specific COX inhibitor) was synergistic for the acute and inflammatory phases of the formalin test. To test this hypothesis further, we repeated similar experiments with rofecoxib (a selective COX-2 inhibitor) and also measured the local concentrations of anandamide, and of two fatty-acid amides, oleoylethanolamide and palmitoylethanolamide. We established the ED(50) for anandamide (34.52 pmol+/-17.26) and rofecoxib (381.72 pmol+/-190.86) and showed that the analgesic effect of the combination was synergistic. We also found that paw tissue levels of anandamide, oleoylethanolamide and palmitoylethanolamide were significantly higher when anandamide was combined with NSAIDs and that this effect was greater with rofecoxib. In conclusion, local injection of anandamide or rofecoxib was antinociceptive in a test of acute and inflammatory pain and the combination of anandamide with rofecoxib was synergistic. Finally, locally injected anandamide with either NSAID (ibuprofen or rofecoxib) generates higher amount of fatty-acid ethanolamides. The exact comprehension of the mechanisms involved needs further investigation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal - C.P. 6128, Succ. Centre-ville, Montréal, Québec, Canada H2W 1T8.
authors.forename: Josée
authors.initials: J
authors.lastname: Guindon
authors.forename: Jesse
authors.initials: J
authors.lastname: LoVerme
authors.forename: André
authors.initials: A
authors.lastname: De Léan
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Pierre
authors.initials: P
authors.lastname: Beaulieu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D063388:Endocannabinoids; D005557:Formaldehyde; D007052:Ibuprofen / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D009578:Nitrobenzenes / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D007783:Lactones; D009578:Nitrobenzenes; D053284:Polyunsaturated Alkamides; D013449:Sulfonamides; D013450:Sulfones; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C116926:rofecoxib; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005557:Formaldehyde; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide; D007052:Ibuprofen