Jn. Francischi et al., Anti-inflammatory and analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis, EUR J PHARM, 399(2-3), 2000, pp. 243-249
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.