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 pmol/paw) 30 min prior to ipsilateral injection of capsaicin (0.1 mu g/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 ETB receptor agonists 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 endothelin ETA receptor antagonist), 10 min before endothelin-1 (10 pmol/paw), fully blocked the hyperalgesic response, whereas similar treatment with the selective endothelin ETB receptor antagonist BQ-788 (i.e., N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine) was ineffective. Intravenous injection of bosentan (17 and 52 mu mol/kg a non-peptidic mixed endothelin ETA/ETB receptor antagonist) or EMS 182874 (i.e., 5-[dimethylamino]-N-[3,4-dimethyl-5-isoxazolyl]-1-naphthalenesulphonamide; 10 and 30 mu mol/kg; a non-peptidic selective endothelin ETA 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 ETB receptor agonist IRL 1620 teach at 30 pmol/paw). Therefore, local endothelin-1 exerts a dual influence in this model: at low doses it causes endothelin ETA 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 ETB) receptors. (C) 1998 Elsevier Science B.V. All rights reserved.