Roles of endothelin ETA and ETB receptors in nociception and chemical, thermal and mechanical hyperalgesia induced by endothelin-1 in the rat hindpaw

Evidence on the relative roles of endothelin ETA and ETB receptors in mediating the nociceptive and hyperalgesic actions of endothelin-1 is still fragmented and conflicting, due to variations between species and/or models. This study assesses the participation of ETA and ETB receptors on the nociceptive behavior and hyperalgesia to chemical (formalin), mechanical and thermal stimuli evoked by endothelin-1 injected into the rat hind-paw. Intraplantar (i.pl.) injection of endothelin-1 (1-30 pmol, 50 μl) induced dose-dependent nociceptive behaviors over the first hour. Endothelin-1 (3–30 pmol) also potentiated both phases of nociception induced by a subsequent ipsilateral i.pl. injection of formalin (0.5%, 50 μl). Endothelin-1, at 10 pmol, increased responses of the first phase (0–10 min) by 97% and of the second phase (15–60 min) by 120%, and similar degrees of potentiation were observed following 30 pmol of the peptide. Endothelin-1 (1–30 pmol) caused slowly developing long-lasting thermal and mechanical hyperalgesia with maximum effects at 10 and 30 pmol, respectively, reaching significance at 2–3 h and remaining elevated for up to at least 8 h after injection. Treatment with the selective ETA and ETB peptidic antagonists BQ-123 and BQ-788 (i.pl., both at 10 nmol, 3.5 h after ET-1 injection) or with the non-peptidic antagonists atrasentan and A-192621 systemically (i.v., 10 and 20 mg/kg, respectively) each caused significant reductions in endothelin-1-induced nociception, as well as chemical, thermal and mechanical hyperalgesia. Thus, the nociceptive and hyperalgesic effects induced by i.pl. endothelin-1 seem to be mediated by both ETA and ETB receptors.