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 factor-alpha (TNF-alpha) levels and/or function in rheumatoid arthritis. The elevation of intracellular levels of cyclic AMP in leukocytes by phosphodiesterase 4 inhibitors is accompanied by significant inhibition of the production of TNF-alpha. Nevertheless, these drugs may enhance the hyperalgesia induced by a range of inflammatory mediators, including TNF-alpha. In the present study, we examined the effects of the phosphodiesterase 4 inhibitor rolipram on the local inflammatory infiltrate and hyperalgesia in a rat model of adjuvant-induced arthritis. Rolipram (3 mg/kg) was administered by oral gavage from day 10 to 14 after disease induction. Pretreatment with rolipram abrogated oedema formation and significantly inhibited hyperalgesia. Histopathological analysis revealed a marked inhibition of cellular influx as well as bone and cartilage destruction. Serum and local TNF-alpha levels were suppressed in treated animals whereas there were little changes in interleukin-1 beta levels. Although cyclic AMP elevating agents may affect nociceptor threshold to increase the hyperalgesic responses acutely, they also possess significant anti-inflammatory activity, which may hinder local mediator release and/or action. The anti-inflammatory effects of rolipram predominate during this chronic arthritis model in the rat. (C) 2000 Elsevier Science B.V. All rights reserved.