Endothelins induce ETB receptor-mediated mechanical hypernocicieption in rat hindpaw:: roles of cAMP and protein kinase C

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-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine; endothelin ETB receptor antagonist), but not BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]; endothelin ETA receptor antagonist; each at 30 pmol). The selective endothelin FTB 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( ETB receptors, induce mechanical hypernociception in the rat hindpaw via cAMP formation and activation of the PKC-dependent phosphorylation cascade. (C) 2004 Elsevier B.V. All rights reserved.