Five synthetic prostaglandin E analogs (11-deoxyPGE 1 , 17-phenyl-ol-trinor prostaglandin E 2 , enisoprost, MB28767 and misoprostol) have been evaluated for their ability to produce mechanical hyperalgesia in rats. The Randall-Selitto paw withdrawal model of mechanical hyperalgesia was used.Following intradermal injections (2.5 μl) into the dorsal surface of the hindpaw, each prostaglandin E analog produced a dose-dependent (1-1000 ng) decrease in nociceptive threshold (i.e. hyperalgesia). Hyperalgesia produced by 17-phenyl-ol-trinor prostaglandin E 2 and MB28767, was inhibited by the prostaglandin E 1 antagonist SC19220 (7.5 ng), while the hyperalgesia produced by 11-deoxyprostaglandin E 1 , enisoprost and misoprostol was not inhibited by this antagonist.Hyperalgesia produced by all five analogs was significantly attenuated or completely blocked by inhibiting stimulatory guanine nucleotide-binding regulatory protein with guanosine 5'-O-(2-thiodiphosphate), adenyl cyclase with 2'5'-dideoxyadenosine and protein kinase A with WIPTIDE.These results suggest the presence of more than one prostaglandin E-receptor subtype, which mediate hyperalgesia, predominantly via the cAMP second messenger system, in the hindpaw of the rat.