title: Janus kinase 2 activation participates in prostaglandin E2-induced hyperalgesia.
abstract: Prostaglandin E2 (PGE2) is one of the major signaling molecules involved in hyperalgesia, acting directly on nociceptors and resulting in the activation of PKA and PKC. Once active, these kinases phosphorylate many cellular proteins, resulting in changes on nociceptors sensorial transduction properties. The Janus Kinases (JAKs) are a family of intracellular signaling molecules generally associated with cytokine signaling, and their activity can be increased in nociceptors after peripheral inflammation. However, there are no evidences of JAKs direct involvement in PGE2 mediated sensitization of nociceptors. Therefore, the aim of the present study was to explore a possible role for JAKs in PGE2 mediated sensitization. In cultured dorsal root ganglion (DRG) neurons, we observed that the administration of PGE2 increases capsaicin induced calcium transients, and a pre-incubation of DRG cells with the JAK inhibitor AG490 blocks this PGE2 in vitro effect. Intrathecal administration of AG490 to ten-weeks-old male Wistar rats reduces the hyperalgesia induced by the intraplantar administration of PGE2 or carrageenan in the right hind paw. We also observed that carrageenan administration in the right hind paw induced an increase in membrane associated PKCepsilon in the ipsilateral L5 DRG, and this increase was blocked by intrathecal AG490 administration. In conclusion the present study indicates that the JAKs expressed in the DRG and spinal cord may have a role in the sensitization of nociceptors by a peripheral inflammatory event. Moreover, the inhibition of JAKs may be a possible novel pharmacological target for the control of the inflammatory hyperalgesia.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil. Electronic address: a008093@dac.unicamp.br.
authors.forename: André Schwambach
authors.initials: AS
authors.lastname: Vieira
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil.
authors.forename: Dionéia
authors.initials: D
authors.lastname: Araldi
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil.
authors.forename: Elayne Vieira
authors.initials: EV
authors.lastname: Dias
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil.
authors.forename: Filipe César
authors.initials: FC
authors.lastname: do Prado
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil.
authors.forename: Claudia Herrera
authors.initials: CH
authors.lastname: Tambeli
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, 13083-970 Campinas, SP, Brazil.
authors.forename: Carlos Amilcar
authors.initials: CA
authors.lastname: Parada
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000276:immunology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D017208:Rats, Wistar; D020032:Tyrphostins / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D002351:Carrageenan; D053614:Janus Kinase 2; D015232:Dinoprostone
keywords: Inflammatory hyperalgesia; Janus kinase; PGE2; PKC