The peripheral pro-nociceptive state induced by repetitive inflammatory stimuli involves continuous activation of protein kinase A and protein kinase C epsilon and its Na V1.8 sodium channel functional regulation in the primary sensory neuron

Abstract

In the present study, the participation of the Na V1.8 sodium channel was investigated in the development of the peripheral pro-nociceptive state induced by daily intraplantar injections of PGE 2 in rats and its regulation in vivo by protein kinase A (PKA) and protein kinase C epsilon (PKCɛ) as well. In the prostaglandin E 2 (PGE 2)-induced persistent hypernociception, the Na V1.8 mRNA in the dorsal root ganglia (DRG) was up-regulated. The local treatment with dipyrone abolished this persistent hypernociception but did not alter the Na V1.8 mRNA level in the DRG. Daily intrathecal administrations of antisense Na V1.8 decreased the Na V1.8 mRNA in the DRG and reduced ongoing persistent hypernociception. Once the persistent hypernociception had been abolished by dipyrone, but not by Na V1.8 antisense treatment, a small dose of PGE 2 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 Na V1.8 mRNA up-regulation in the DRG. In addition, during the persistent hypernociceptive state, the PKA and PKCɛ expression and activity in the DRG are up-regulated and the administration of the PKA and PKCɛ inhibitors reduce the hypernociception as well as the Na V1.8 mRNA level. In the present study, we demonstrated that the functional regulation of the Na V1.8 mRNA by PKA and PKCɛ 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.