Inhibition of Noxious Stimulus‐Induced Spinal Prostaglandin E2 Release by Flurbiprofen Enantiomers

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 ∼ 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^‐1S‐ 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^‐1R‐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 (∼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.