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

Abstract

Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E 2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenaseinhibiting 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 Rflurbiprofen acts via inhibition of spinal PG release, concentrations of PGE 2 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 Ϫ1 , 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 PGE 2 dialysate concentrations were 100.6 Ϯ 6.4 pg ml Ϫ1 (mean Ϯ SEM). After formalin injection they rose about threefold with a maximum of 299.4 Ϯ 68.4 pg ml Ϫ1 at 7.5 min. After ϳ1 h PGE 2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE 2 release and reduced PGE 2 concentrations below basal levels. S-and R-flurbiprofen at 9 mg kg Ϫ1 produced a minimum of 15.8 Ϯ 5.2 and 27.7 Ϯ 14.9 pg ml Ϫ1 , respectively, and 27 mg kg Ϫ1 S-and R-flurbiprofen resulted in 11.7 Ϯ 1.7 and 9.3 Ϯ 4.7 pg ml Ϫ1 , respectively. PGE 2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg Ϫ1 R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE 2 concentrations were not affected. S-Flurbiprofen (27 mg kg Ϫ1 ), however, led to a moderate reduction (ϳ40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE 2 release and support the current view that increased spinal PGE 2 release significantly contributes to nociceptive processing.

Increased Tumor Necrosis Factor-α and Prostaglandin E2 Concentrations in the Cerebrospinal Fluid of Rats with Inflammatory Hyperalgesia: The Effects of Analgesic Drugs

“…These data indicate that spinal PGE 2 is involved in pain initiated by acute peripheral inflammation. In other experiments, it has been demonstrated that PGE 2 increase, as well as the associated behavior, can be prevented by the administration of analgesic drugs such as paracetamol and flurbiprofen (26,27).…”

R-flurbiprofen, a novel nonsteroidal anti-inflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro

“…COX-2 expression at this level is influenced by COX-independent signal transduction pathways and transcriptional activation mediated by NF-jB, an inducible transcription factor that activates the transcription of various inflammatory cytokines, adhesion molecules, enzymes and chemokines, and activator protein 1 (AP-1) [50,51]. R-flurbiprofen has been shown to inhibit NF-jB and AP-1 DNA-binding activity in a dosedependent manner, which may inhibit NF-jB-dependent gene transcription [8]. Therefore, it is postulated that R-flurbiprofen may act as an apoptotic agent via COX-2 down-regulation through inhibition of NF-jB.…”

“…R-flurbiprofen, a 2-arylpropionic acid, is a novel nonsteroidal anti-inflammatory drug (NSAID) derivative that has been shown to have antinociceptive and antitumorigenic effects both in vitro and in vivo in various animal models of colon and prostate cancer [4][5][6][7][8][9]. R-flurbiprofen does not directly enzymatically inhibit either cyclooxygenase-1 (COX-1) or COX-2 but instead appears to act through COX-independent mechanisms.…”

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

“…Interestingly, R-flurbiprofen does not inhibit cyclooxygenase activity [4] and has been considered as the non-functional constituent of marketed flurbiprofen-racemate. However, R-flurbiprofen reduces inflammation [5] via inhibition of the transcription factor NF-κB [5] and is essentially free of the side effects typical to classical NSAIDs, such as gastrointestinal or renal toxicity [6].…”