Increasing evidence indicates that
endothelin-1 (ET-1) activates nociceptive neurons and sensitizes them to different noxious stimuli, but involvement of TRPV1-dependent mechanisms in mediation of such effects is not yet fully understood. Here we report that intraplantar (i.pl.) injection of ET-1 (10 pmol) into the hind paw of rats induced overt nociceptive behavior over the first hour, followed by a slowly developing
thermal hyperalgesia, lasting from 3 to 8h after injection. Both effects were also induced by similar
injections of
capsaicin (10-1000 pmol), but these responses were shorter lasting than those caused by ET-1. Local pre-treatment with the TRPV1 antagonist
capsazepine (30 nmol, i.pl.) reduced only the
thermal hyperalgesia induced by ET-1, but fully suppressed both responses to
capsaicin (1000 pmol). Injection of a sub-threshold dose of ET-1 (0.1 pmol, i.pl.) prior to
capsaicin (1 pmol, i.pl.) markedly sensitized the hind paw to the overt nociceptive and thermal hyperalgesic effects of the later. The potentiation of
capsaicin-induced nociception by ET-1 was abolished by prior i.pl. injection of
BQ-123 (ET(A) receptor antagonist, 10 nmol), but unaffected by
BQ-788 (ET(B) receptors antagonist, 10 nmol), whereas the enhancement of
capsaicin-induced
hyperalgesia by ET-1 was attenuated by both antagonists. Therefore, differently to what has been reported in mice, in rats TRPV1 receptors contribute selectively to
thermal hyperalgesia, but not overt nociception, induced by ET-1. Importantly, although ET-1 augments
capsaicin-induced overt nociception and
thermal hyperalgesia, potentiation of the former relies solely on ET(A) receptor-mediated signaling mechanisms, whereas both receptors contribute to the latter.