In this study we have evaluated the mechanisms mediating the prolonged hyperalgesia induced by administration of prostaglandin E2 plus rolipram, an inhibitor of type IV phosphodiesterase. The Randall-Selitto paw pressure device was employed to measure the effect of intradermal injection of test agents on the time course of the decrease in mechanical nociceptive threshold produced by prostaglandin E2 plus rolipram in the hairy skin of the hindpaw of the rat. The intradermal injection of prostaglandin E2 produced a dose-dependent decrease in the nociceptive threshold which lasted approximately 2 h. While rolipram alone had no significant effect on nociceptive threshold, it enhanced and prolonged (> 72 h) prostaglandin E2-induced hyperalgesia. WIPTIDE, a protein kinase A inhibitor, when administered 30 min after prostaglandin E2, or with prostaglandin E2 plus rolipram, a time when prostaglandin E2-induced hyperalgesia was at its peak, produced a significant reduction in hyperalgesia. However, at 90 or at 180 min after injection of prostaglandin E2 plus rolipram, WIPTIDE was found to be without effect. H-8, a protein kinase G inhibitor, and okadaic acid, a protein phosphatase inhibitor, when administered 30 min after prostaglandin E2, or 180 min after prostaglandin E2 plus rolipram, produced no significant effect. However, when administered 90 min after prostaglandin E2 plus rolipram, each produced a significant reduction in the hyperalgesia induced by prostaglandin E2 plus rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)