In this study we eliminated known indirect hyperalgesic mechanisms by blocking the cyclooxygenase pathway of arachidonic acid metabolism with indomethacin, depleting sympathetic postganglionic neurons with 6-hydroxydopamine and depleting polymorphonuclear leukocytes with hydroxyurea. These treatments did not significantly affect the dose-dependence relationship for prostaglandin E2 (PGE2)- and prostaglandin I2 (PGI2)-induced changes in the mechanical nociceptive threshold in the rat. These data are compatible with the hypothesis that PGE2 and PGI2 act directly on peripheral terminals of nociceptive afferents to produce hyperalgesia.