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In the present study, the participation of the NaV1.8 sodium channel was investigated in the development of the peripheral pro-nociceptive state induced by daily intraplantar injections of PGE2 in rats and its regulation in vivo by protein kinase A (PKA) and protein kinase C epsilon (PKCε) as well. In the prostaglandin E2 (PGE2)-induced persistent hypernociception, the NaV1.8 mRNA in the dorsal root ganglia (DRG) was up-regulated. The local treatment with dipyrone abolished this persistent hypernociception but did not alter the NaV1.8 mRNA level in the DRG. Daily intrathecal administrations of antisense NaV1.8 decreased the NaV1.8 mRNA in the DRG and reduced ongoing persistent hypernociception. Once the persistent hypernociception had been abolished by dipyrone, but not by NaV1.8 antisense treatment, a small dose of PGE2 restored the hypernociceptive plateau. These data show that, after a period of recurring inflammatory stimuli, an intense and prolonged nociceptive response is elicited by a minimum inflammatory stimulus and that this pro-nociceptive state depends on NaV1.8 mRNA up-regulation in the DRG. In addition, during the persistent hypernociceptive state, the PKA and PKCε expression and activity in the DRG are up-regulated and the administration of the PKA and PKCε inhibitors reduce the hypernociception as well as the NaV1.8 mRNA level. In the present study, we demonstrated that the functional regulation of the NaV1.8 mRNA by PKA and PKCε in the primary sensory neuron is important for the development of the peripheral pro-nociceptive state induced by repetitive inflammatory stimuli and for the maintenance of the behavioral persistent hypernociception.