Endothelin-1-induced ETA receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw:: modulation by simultaneous ETB receptor activation

1 Endothelin-1 causes ETA receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin-1 is also accompanied by other proinflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. 2 Intraplantar (i.pl.) hind-paw injection of endothelin-1 (0.3-30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20.5+/-3.3 s; endothelin-1 at 30 pmol, 78.1+/-9.8 s), largely confined to the first 15 min. Endothelin-1 (1-10 pmol) potentiated ipsilateral capsaicin-induced (0.1 mu g, i.pl.; at 30 min) nociception (vehicle, 40.2+/-2.6s; endothelin-1 at 10 pmol, 98.4+/-5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+/-2.3 mg; endothelin-1 at 30 pmol, 100.3+/-6.1 mg). 3 Selective ETB receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. 4 ETA receptor antagonists BQ-123 (1 nmol, i.pl.) or A-127722-5 (6 mu mol kg(-1) i.v.) prevented all effects of endothelin-1 (10 pmol), but the ETB receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineffective. 5 BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmoI endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. 6 Thus, endothelin-1 triggers ETA receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ETB receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide.