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

• Published in: European journal of pharmacology 2000-07, Vol.399 (2), p.243-249
• Main Authors: Francischi, Janetti N, Yokoro, Celina M, Poole, S, Tafuri, Wagner L, Cunha, Fernando Q, Teixeira, Mauro M
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Analgesics - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Arthritis; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Experimental - physiopathology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Edema - physiopathology; Edema - prevention & control; Female; Hindlimb; Hyperalgesia; Inflammation - pathology; Inflammation - prevention & control; Interleukin-1 - metabolism; Medical sciences; Oedema; Pharmacology. Drug treatments; Phosphodiesterase 4; Phosphodiesterase Inhibitors - pharmacology; Rats; Rolipram; Rolipram - pharmacology; Time Factors; TNF-α (tumor necrosis factor-α); Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00330-7

There has been much interest in strategies which modulate tumour necrosis factor-α (TNF-α) 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-α. Nevertheless, these drugs may enhance the hyperalgesia induced by a range of inflammatory mediators, including TNF-α. 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-α levels were suppressed in treated animals whereas there were little changes in interleukin-1β 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.