Role of ET(A) and ET(B) endothelin receptors on endothelin-1-induced potentiation of nociceptive and thermal hyperalgesic responses evoked by capsaicin in rats.
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.
Department of Pharmacology, Universidade Federal de Santa Catarina, Center of Biological Sciences, Block D, Florianopolis, 88049-490, SC, Brazil.
Emerson Marcelo
EM
Motta
Juliana Geremias
JG
Chichorro
Giles Alexander
GA
Rae
D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006614:Hindlimb / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement; D010456:Peptides, Cyclic / Q000494:pharmacology; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D013696:Temperature
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C086539:BQ 788; C071423:capsazepine; D002211:Capsaicin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)