Endothelins induce ETB receptor-mediated mechanical hypernociception 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 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.
Department of Pharmacology, Faculty of Medicine, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil.
Joice M
JM
da Cunha
Giles A
GA
Rae
Sérgio H
SH
Ferreira
Fernando de Q
Fde Q
Cunha
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D006614:Hindlimb / Q000187:drug effects / Q000502:physiology; D008297:Male; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000819:agonists / Q000502:physiology*
D016232:Endothelins; D044023:Receptor, Endothelin B; D000242:Cyclic AMP; D011493:Protein Kinase C