Effects of endothelin-1 on capsaicin-induced nociception in mice

Abstract

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 μg/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 (≤30 pmol/paw) and IRL 1620 (i.e., Suc[Glu 9,Ala 11,15]endothelin-1-(10–21); ≤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- γ-methylleucyl- d-1-methoxycarboyl- d-norleucine) was ineffective. Intravenous injection of bosentan (17 and 52 μmol/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-naphthalenesulphonamide; 10 and 30 μmol/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.