EFFECTS OF ENDOTHELIN-1 ON CAPSAICIN-INDUCED NOCICEPTION IN MICE

The influence of endothelin-1 on nociception induced by capsaicin was assessed in the mouse hindpaw. Local endothelin-1 injection (1 to 20 p mol/paw) 30 min prior to ipsilateral injection of capsaicin (0.1 mu g/ paw) increased, in a graded fashion, the time spent licking the inject ed paw. Maximal hyperalgesia was obtained with 10 pmol/paw of endothel in-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 ETB receptor agonis ts sarafotoxin S6c (less than or equal to 30 pmol/paw) and IRL 1620 (i .e., Suc[Glu(9),Ala(11,15)]endothelin-1-(10-21), less than or equal to 100 pmol/paw) failed to induce hyperalgesia. Local treatment with BQ- 123 (i.e., cyclo[DTrp-DAsp-Pro-DVal-Leu] 1 nmol/paw selective endothel in ETA receptor antagonist), 10 min before endothelin-1 (10 pmol/paw), fully blocked the hyperalgesic response, whereas similar treatment wi th the selective endothelin ETB receptor antagonist BQ-788 (i.e., amma -methylleucyl-D-1-methoxycarboyl-D-norleucine) was ineffective. Intrav enous injection of bosentan (17 and 52 mu mol/kg a non-peptidic mixed endothelin ETA/ETB receptor antagonist) or EMS 182874 (i.e., -dimethyl -5-isoxazolyl]-1-naphthalenesulphonamide; 10 and 30 mu mol/kg; a non-p eptidic selective endothelin ETA receptor antagonist), 1 h before endo thelin-1, inhibited its hyperalgesic effect in a graded fashion and ab olished the response at the higher doses. None of the antagonists modi fied nociception induced by capsaicin alone or the hyperalgesia induce d by local injection of 5-hydroxytryptamine (5-HT; 2 nmol/paw, 30 min before capsaicin). Hyperalgesia induced by 5-HT was abolished by simul taneous injection of endothelin-1 or the endothelin ETB receptor agoni st IRL 1620 teach at 30 pmol/paw). Therefore, local endothelin-1 exert s a dual influence in this model: at low doses it causes endothelin ET A receptor-mediated hyperalgesia (i.e., it potentiates capsaicin-induc ed nociception), whereas at higher doses it induces an anti-hyperalges ic effect against 5-HT which seems to be mediated via distinct endothe lin ET (possibly ETB) receptors. (C) 1998 Elsevier Science B.V. All ri ghts reserved.