Anti-inflammatory and analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis

There has been much interest in strategies which modulate tumour necrosis f actor-alpha (TNF-alpha) levels and/or function in rheumatoid arthritis. The elevation of intracellular levels of cyclic AMP in leukocytes by phosphodi esterase 4 inhibitors is accompanied by significant inhibition of the produ ction of TNF-alpha. Nevertheless, these drugs may enhance the hyperalgesia induced by a range of inflammatory mediators, including TNF-alpha. In the p resent study, we examined the effects of the phosphodiesterase 4 inhibitor rolipram on the local inflammatory infiltrate and hyperalgesia in a rat mod el of adjuvant-induced arthritis. Rolipram (3 mg/kg) was administered by or al gavage from day 10 to 14 after disease induction. Pretreatment with roli pram abrogated oedema formation and significantly inhibited hyperalgesia. H istopathological analysis revealed a marked inhibition of cellular influx a s well as bone and cartilage destruction. Serum and local TNF-alpha levels were suppressed in treated animals whereas there were little changes in int erleukin-1 beta levels. Although cyclic AMP elevating agents may affect noc iceptor threshold to increase the hyperalgesic responses acutely, they also possess significant anti-inflammatory activity, which may hinder local med iator release and/or action. The anti-inflammatory effects of rolipram pred ominate during this chronic arthritis model in the rat. (C) 2000 Elsevier S cience B.V. All rights reserved.