Enhanced effects of co-administered dexamethasone and diclofenac on inflammatory pain processing and associated spinal c-Fos expression in the rat.
This study determines the effects of dexamethasone versus co-administered dexamethasone and diclofenac, on carrageenan-evoked spinal c-Fos expression and peripheral oedema in the freely moving rat. Drugs were administered intravenously 25 min before intraplantar injection of carrageenan (6 mg/150 microliters of saline). Three hours later the number of spinal c-Fos-LI neurones and peripheral oedema were assessed. The total number of control carrageenan-evoked c-Fos-LI neurones in the lumbar spinal cord was 121 +/- 5 labelled neurones per section, segments L4-L5, which were predominantly located in the superficial and deep laminae (41 +/- 3% and 40 +/- 2% of the total number of c-Fos-LI neurones per section, respectively) of the dorsal horn of the spinal cord. Pre-administered dexamethasone (0.05, 0.10 and 0.50 mg/kg i.v.) dose-dependently reduced the total number of c-Fos-LI neurones (30 +/- 4%, 52 +/- 3% and 58 +/- 2% reduction, respectively), with effects of the higher doses being strongest on the deep laminae c-Fos-LI neurones. The effects of dexamethasone on the total number of c-Fos-LI neurones and the peripheral oedema were positively correlated. Co-administration of low doses of dexamethasone and diclofenac (0.025 + 1.5 mg/kg i.v. respectively), which had negligible effects when administered separately, greatly reduced both the total number of carrageenan-evoked c-Fos-LI neurones (61 +/- 5% reduction as compared to control value) and the peripheral oedema (80 +/- 8% and 60 +/- 5% reduction for ankle and paw oedema, respectively). The attenuation by co-administered dexamethasone and diclofenac, of both c-Fos expression and the peripheral oedema, was significantly greater than the effect of dexamethasone alone (P < 0.001 for both) and diclofenac alone (P < 0.001 for both). Our study illustrates enhanced attenuating effects of co-administered dexamethasone and diclofenac on both inflammatory oedema and the associated spinal expression of c-Fos, an indicator of nociceptive transmission at the spinal level. The apparent interactions between the mechanisms of action of NSAIDs and steroids suggest that co-therapy may produce beneficial inflammatory and pain relief in the absence of excessive side effects.
Buritova
Jaroslava
J
Unité de Recherches de Physiopharmacologie du Système Nerveux, INSERM U161 and EPHE, Paris, France.
Honoré
Prisca
P
Chapman
Victoria
V
Besson
Jean-Marie
JM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004008:Diclofenac / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D010146:Pain / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016760:Proto-Oncogene Proteins c-fos; D004008:Diclofenac; D003907:Dexamethasone; D002351:Carrageenan