title: Inhibition of noxious stimulus-induced spinal prostaglandin E2 release by flurbiprofen enantiomers: a microdialysis study.
abstract: Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
authors.affiliation: Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. geisslinger@em.uni-frankfurt.de
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
authors.forename: U
authors.initials: U
authors.lastname: Muth-Selbach
authors.forename: O
authors.initials: O
authors.lastname: Coste
authors.forename: G
authors.initials: G
authors.lastname: Vetter
authors.forename: A
authors.initials: A
authors.lastname: Schrödter
authors.forename: H G
authors.initials: HG
authors.lastname: Schaible
authors.forename: K
authors.initials: K
authors.lastname: Brune
authors.forename: I
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001769:Blood / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D005480:Flurbiprofen / Q000494:pharmacology*; D005557:Formaldehyde / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects; D009994:Osmolar Concentration; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D013237:Stereoisomerism; D013268:Stimulation, Chemical
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D005557:Formaldehyde; D005480:Flurbiprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone