Endothelin (ET)-1 evokes a burning pruritus sensation when injected intradermally in humans and nocifensive behavior when injected into the hind paw of rodents. Because pain and pruritus are clearly distinct nociceptive sensory modalities in humans, the current study evaluates the potential of ET-1 to elicit scratching behavior in mice. Mice received an intradermal injection of 1-30 pmol ET-1; 10 microg of the mast cell degranulator compound, 48/80; 100 nmol histamine; or vehicle into the scruff, and the number of scratching bouts displayed during the first 40 mins was recorded. ET-1 caused dose-dependent scratching bouts, which, like the responses to histamine and compound 48/80, occurred mainly during the first 5 to 10 mins of injection, but fewer episodes were also seen up to 35 mins. The effect of ET-1 was maximal at 10 pmol (total 40 +/- 7 bouts), a value similar to that caused by histamine (52 +/- 5 bouts) and compound 48/80 (53 +/- 6 bouts). The selective ET(B) receptor agonist, IRL-1620 (10 pmol), was not pruritic per se, and actually inhibited responses to histamine and ET-1. Pruritus induced by ET-1 was inhibited by the ET(A) receptor antagonists, 10 nmol BQ-123 (co-injected; net inhibition, 87%) and 10 mg/kg atrasentan (intraperitoneal administration; net inhibition, 83%), or the ET(B) receptor antagonist, 20 mg/kg A-192621 (intraperitoneal administration; net inhibition, 64%), but the response was augmented by co-injection of the ET(B) receptor antagonist, 3 nmol BQ-788 (net potentiation, 234%). Responses to compound 48/80 or responsiveness of vehicle-treated mice were unaffected by these antagonists. Thus, ET-1 displays potent pruritic actions in the mouse mediated to a substantial extent via local ET(A) receptors. The findings with IRL-1620 and BQ-788 suggest that local ET(B) receptors exert an antipruritic role, but, for reasons still unknown, the results obtained using systemic A-192621 injection are at variance with this view.