The nonsteroidal anti-inflammatory drugs are presumed to produce their analgesic effects by inhibiting the cyclooxygenase catalyzed metabolism of arachidonic acid to hyperalgesic prostanoids. This study examined the hyperalgesic effect of a range of prostaglandins. We found, employing the rat paw-withdrawal test, that while intradermal injection of the known hyperalgesic prostaglandins, E2 and I2, produced hyperalgesia, other primary metabolites of the cyclooxygenation of arachidonic acid (prostaglandin F2 alpha, prostaglandin D2, thromboxane B2 and 12(S) hydroxyheptadecatrienoic acid) did not produce hyperalgesia. We conclude that prostaglandin E2 and prostaglandin I2 are the main hyperalgesic metabolites of the cyclooxygenase pathway of arachidonic acid.