The influence of endothelin-1 on nociception induced by capsaicin was assessed in the mouse hindpaw. Local endothelin-1 injection (1 to 20 pmol/paw) 30 min prior to ipsilateral injection of capsaicin (0.1 microg/paw) increased, in a graded fashion, the time spent licking the injected paw. Maximal hyperalgesia was obtained with 10 pmol/paw of endothelin-1 (capsaicin-induced hindpaw licking time increased from 43 +/- 3 s to 114 +/- 7 s, n = 6), but no hyperalgesia was evident following 30 pmol/paw of endothelin-1. The selective endothelin ET(B) receptor agonists sarafotoxin S6c (< or = 30 pmol/paw) and IRL 1620 (i.e., Suc[Glu9,Ala11,15]endothelin-1-(10-21); < or = 100 pmol/paw) failed to induce hyperalgesia. Local treatment with BQ-123 (i.e., cyclo[DTrp-DAsp-Pro-DVal-Leu] 1 nmol/paw selective endothelin ET(A) receptor antagonist), 10 min before endothelin-1 (10 pmol/paw), fully blocked the hyperalgesic response, whereas similar treatment with the selective endothelin ET(B) receptor antagonist BQ-788 (i.e., N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D- 1-methoxy-carboyl-D-norleucine) was ineffective. Intravenous injection of bosentan (17 and 52 micromol/kg a non-peptidic mixed endothelin ET(A)/ET(B) receptor antagonist) or BMS 182874 (i.e., 5-[dimethylamino]-N-[3,4-dimethyl-5-isoxazolyl]-1-naphthalenesulph onamide; 10 and 30 micromol/kg; a non-peptidic selective endothelin ET(A) receptor antagonist), 1 h before endothelin-1, inhibited its hyperalgesic effect in a graded fashion and abolished the response at the higher doses. None of the antagonists modified nociception induced by capsaicin alone or the hyperalgesia induced by local injection of 5-hydroxytryptamine (5-HT; 2 nmol/paw, 30 min before capsaicin). Hyperalgesia induced by 5-HT was abolished by simultaneous injection of endothelin-1 or the endothelin ET(B) receptor agonist IRL 1620 (each at 30 pmol/paw). Therefore, local endothelin-1 exerts a dual influence in this model: at low doses it causes endothelin ET(A) receptor-mediated hyperalgesia (i.e., it potentiates capsaicin-induced nociception), whereas at higher doses it induces an anti-hyperalgesic effect against 5-HT which seems to be mediated via distinct endothelin ET (possibly ET(B)) receptors.