title: Involvement of nuclear factor kappa B in the maintenance of persistent inflammatory hypernociception.
abstract: The pathophysiology of chronic inflammatory pain remains poorly understood. In this context, we developed an experimental model in which successive daily injection of prostaglandin E2 (PGE2) for 14days into rat hind paws produces a persistent state of hypernociception (i.e. decrease in mechanical nociceptive threshold). This state persists for more than 30days after discontinuing PGE2 injection. In the present study, we investigated the participation of nuclear factor kappa B (NF-κB), in the maintenance of this process. Mechanical hypernociception was evaluated using the electronic von Frey test. Activation of NF-κB signaling was measured through the determination of NF-κB p65 subunit translocation to the nucleus of dorsal root ganglion neurons (DRG) by immunofluorescence and western blotting. Herein, we detected an increase in NF-κB p65 subunit translocation to the nucleus of DRG neurons along with persistent inflammatory hypernociception compared with controls. Intrathecal treatment with either dexamethasone or PDTC (NF-κB activation inhibitor) after ending of the induction phase of the persistent inflammatory hypernociception, curtailed the hypernociception period as well as reducing NF-κB p65 subunit translocation. Treatment with antisense oligonucleotides against the NF-κB p65 subunit for 5 consecutive days also reduced persistent inflammatory hypernociception. Inhibition of PKA and PKCε reduced persistent inflammatory hypernociception, which was associated with inhibition of NF-κB p65 subunit translocation. Together these results suggest that peripheral activation of NF-κB by PKA and PKC in primary sensory neurons plays an important role in maintaining persistent inflammatory pain.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Guilherme R
authors.initials: GR
authors.lastname: Souza
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Rangel L
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Instituto de Ciências Biomédicas, Federal University of Uberlandia, Umuarama, MG 38405-320 Uberlândia, Brazil.
authors.forename: Celina M
authors.initials: CM
authors.lastname: Lotufo
authors.affiliation: Departamento de Ciencias Patologicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Mani I
authors.initials: MI
authors.lastname: Funez
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Christiane F
authors.initials: CF
authors.lastname: Villarreal
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Jhimmy
authors.initials: J
authors.lastname: Talbot
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parada
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. Electronic address: fdqcunha@fmrp.usp.br.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. Electronic address: shferrei@fmrp.usp.br.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D059226:Nociceptive Pain / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016328:NF-kappa B; D017868:Cyclic AMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon
keywords: Chronic inflammatory pain; Dorsal root ganglion; Nuclear factor kappa B; PKA; PKC; Primary sensory neuron