title: A role for endocannabinoids in indomethacin-induced spinal antinociception.
abstract: Inhibition of prostaglandins synthesis does not completely explain non-steroidal anti-inflammatory drug-induced spinal antinociception. Among other mediators, endocannabinoids are involved in pain modulation. Indomethacin-induced antinociception, in the formalin test performed in spinally microdialysed mice, was reversed by co-administration of the cannabinoid 1 (CB(1)) antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (AM-251), but not by co-infusion of prostaglandin E(2). Indomethacin was ineffective in CB(1) knockout mice. AM-251 also reversed the indomethacin-induced antinociception in a test of inflammatory hyperalgesia to heat. Furthermore, during the formalin test, indomethacin lowered the levels of spinal nitric oxide (NO), which activates cellular reuptake and thus breakdown of endocannabinoids. The pronociceptive effect of an NO donor, 3-methyl-N-nitroso-sydnone-5-imine (RE-2047), was abolished by co-administration of the endocannabinoid transporter blocker N-(4-hydroxyphenyl) arachidonoyl amide (AM-404). Moreover, the antinociceptive activity of the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), was reversed by AM-251. Thus we propose that at the spinal level, indomethacin induces a shift of arachidonic acid metabolism towards endocannabinoids synthesis secondary to cyclooxygenase inhibition. In addition, it lowers NO levels with subsequent higher levels of endocannabinoids.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, AVENTIS Pharma Deutschland GmbH, Fahrstrasse 17, D-91054 Erlangen, Germany. hans.guehring@Aventis.com
authors.forename: Hans
authors.initials: H
authors.lastname: Gühring
authors.forename: May
authors.initials: M
authors.lastname: Hamza
authors.forename: Marina
authors.initials: M
authors.lastname: Sergejeva
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ates
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Kotalla
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D063385:Cannabinoid Receptor Modulators; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000235:genetics; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology
chemical_list: D000700:Analgesics; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D007527:Isoenzymes; D008565:Membrane Proteins; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D007213:Indomethacin