• D Sachs, Cf Villarreal, Fq Cunha, Ca Parada, and Sh Ferreira.
• Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
• Br. J. Pharmacol. 2009 Mar 1;156(5):826-34.

Background And PurposeProtein kinase (PK) A and the epsilon isoform of PKC (PKCepsilon) are involved in the development of hypernociception (increased sensitivity to noxious or innocuous stimuli) in several animal models of acute and persistent inflammatory pain. The present study evaluated the contribution of PKA and PKCepsilon to the development of prostaglandin E(2) (PGE(2))-induced mechanical hypernociception.Experimental ApproachProstaglandin E(2)-induced mechanical hypernociception was assessed by constant pressure rat paw test. The activation of PKA or PKCepsilon was evaluated by radioactive enzymic assay in the dorsal root ganglia (DRG) of sensory neurons from the hind paws.Key ResultsHypernociception induced by PGE(2) (100 ng) by intraplantar (i.pl.) injection, was reduced by i.pl. treatment with inhibitors of PKA [A-kinase-anchoring protein St-Ht31 inhibitor peptide (AKAPI)], PKCepsilon (PKCepsilonI) or adenylyl cyclase. PKA activity was essential in the early phase of the induction of hypernociception, whereas PKC activity was involved in the maintenance of the later phase of hypernociception. In the DRG (L4-L5), activity of PKA increased at 30 min after injection of PGE(2) but PKC activity increased only after 180 min. Moreover, i.pl. injection of the catalytic subunit of PKA induced hypernociception which was markedly reduced by pretreatment with an inhibitor of PKCepsilon, while the hypernociception induced by paw injection of PKCepsilon agonist was not affected by an inhibitor of PKA (AKAPI).Conclusions And ImplicationsTaken together, these findings are consistent with the suggestion that PKA activates PKCepsilon, which is a novel mechanism of interaction between these kinases during the development of PGE(2)-induced mechanical hypernociception.

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