Abstract We have studied prostaglandin E 1-induced mechanical hyperalgesia in the rat hindpaw, by assessing paw-withdrawal thresholds, before and after injecting prostaglandin E 1 alone or with other agents, in normal and streptozotocin-induced diabetic rats. In normal and diabetic rats, prostaglandin E 1 (1–1000 ng) produced a dose-dependent decrease in mechanical nociceptive threshold. In diabetic rats, prostaglandin E 1 was more potent than in normal rats, in producing hyperalgesia, whereas prostaglandin E 2 hyperalgesia was not changed in normal and diabetic rats. Prostaglandin Ei-induced hyperalgesia was not inhibited by E-type 1 prostaglandin receptor antagonists, SC 19220 or SC51089, either in normal or diabetic rats. In fact, in the presence of SC19220, prostaglandin E 1 produced enhanced hyperalgesia, in normal rats. Prostaglandin E 1 hyperalgesia was not significantly modified by sympathectomy or indomethacin. Unlike prostaglandin E 2, prostaglandin E 1 hyperalgesia was not blocked by the inhibitor of the stimulatory guanine nucleotide-binding regulatory protein, guanosine 5'-O-(2-thiodiphosphate). It is suggested that prostaglandin E 1 decreases primary afferent nociceptive threshold directly, by activating a prostaglandin receptor other than the E-type 1 prostaglandin receptor, and that this receptor is not coupled to a stimulatory guanine nucleotide-binding regulatory protein.