PHARMACOLOGICAL CHARACTERIZATION OF SEPHADEX-INDUCED EDEMA IN RAT PAWS - PREDOMINANT ROLE OF SEROTONIN AND PLATELET-ACTIVATING-FACTOR

An intravenous injection of Sephadex beads has been used to induce lun g inflammation and bronchial hyperreactivity in small animals. In the present study, we injected Sephadex beads (0.3-5.5 mg/paw) into rat pa ws and followed the resulting inflammation plethysmometrically. Our re sults show that Sephadex beads induced a significant and dose-dependen t increase in the hindpaw volume at 5 min; it was maximal at 30-60 min and declined at 4 h. However, the paw volume remained significantly i ncreased for up to 21 days. The initial 4-hour-oedema was confirmed by histopathology of the paw tissues, but the persistent increase in paw volume was related to a chronic inflammatory (granulomatous) response . The Sephadex-induced oedema was predominantly due to serotonin (5-HT ) release since specific antagonists such as methysergide (1 mg/kg) an d pizotifen (0.1-2 mg/kg) administered both systemically and locally w ere able to inhibit the oedema (10-100 mu g/paw) as could pretreatment with compound 48/80. In addition, platelet-activating factor (PAF) wa s also shown to be involved, since systemic pretreatment using the spe cific PAF antagonist BN 52021 (1 mg/kg) was able to inhibit the increa se in paw volume induced by Sephadex. Effective doses of indomethacin (2 mg/kg), L-NAME (1 mg/kg), pyrilamine (1-2 mg/kg), ondansetron (1 mg /kg) and HOE 140 (1 mg/kg) did not affect the Sephadex-induced oedema, thus ruling out the participation of prostaglandins, nitric oxide, hi stamine, 5-HT3 receptors and bradykinin in its development. Since the late increases in paw volume induced by Sephadex were reduced by pretr eatment of the animals with the immunosuppressive drugs rapamycin and dexamethasone but not cyclosporin, our results also suggested that dis tinct immunological pathways may be involved in the modulation of the chronic phase of inflammation induced by Sephadex beads in rat paws.