Endothelin-1 (ET-1) induced hyperalgesia in rats, abdominal constrictions in mice, incapacitation in dogs, and, when injected intradermally into humans, caused wheal and flare responses, which were accompanied by itching. The ET-1 induced constrictions in mice were prevented by indomethacin. In contrast, indomethacin had no effect on the hyperalgesic responses in the rat. These results indicate that ET-1 may play a role in modulating pain.