Endothelins induce ET B receptor-mediated mechanical hypernociception in rat hindpaw: roles of cAMP and protein kinase C

Abstract

The present study assesses the capacity of endothelins to induce mechanical hypernociception, and characterises the receptors involved and the contribution of cAMP and protein kinases A (PKA) and C (PKC) to this effect. Intraplantar administration of endothelin-1, endothelin-2 or endothelin-3 (3–30 pmol) induced dose- and time-dependent mechanical hypernociception, which was inhibited by BQ-788 ( N-cys-2,6-dimethylpiperidinocarbonyl- l-γ-methylleucyl- d-1-methoxycarboyl- d-norleucine; endothelin ET B receptor antagonist), but not BQ-123 (cyclo[ d-Trp- d-Asp-Pro- d-Val-Leu]; endothelin ET A receptor antagonist; each at 30 pmol). The selective endothelin ET B receptor agonist BQ-3020 ( N-Ac-Ala 11,15-endothelin-1 (6–21)) fully mimicked the hypernociceptive effects of the natural endothelins. Treatments with indomethacin, atenolol or dexamethasone did not inhibit endothelin-1-evoked mechanical hypernociception. However, endothelin-1-induced mechanical hypernociception was potentiated by the cAMP phosphodiesterase inhibitor rolipram (4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone) and inhibited by the PKC inhibitors staurosporine and calphostin C, but was unaffected by the PKA inhibitor H89 ( N-[2-(( p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide). Thus, endothelins, acting through endothelin ET B receptors, induce mechanical hypernociception in the rat hindpaw via cAMP formation and activation of the PKC-dependent phosphorylation cascade.