title: The antinociceptive effects of the tetracyclic triterpene euphol in inflammatory and neuropathic pain models: The potential role of PKCε.
abstract: Evidences suggest protein kinase C epsilon (PKCε) activation is involved in both inflammatory and neuropathic pains. We have previously shown that tetracyclic triterpene euphol produces antinociception in different models of persistent pain, an action associated with its anti-inflammatory properties. Among these properties are the cannabinoid system activation and different PKC isozymes modulation. Herein, we sought to explore the potential role of PKCε modulation on euphol antinociceptive effect, in inflammatory and neuropathic pain models, in rodents. Also, we investigated further mechanisms associated with euphol effects. Oral treatment with euphol (30 mg/kg) prevented the putative effect of PGE2-induced acute and persistent mechanical hypersensitivity in mice and rats, respectively. In the PGE2-induced acute mechanical hypersensitivity euphol promoted an inhibitory effect similar to a PKCε inhibitor peptide. Likewise, in rats it prevented the mechanical hypersensitivity induced by a PKCε activator. Conversely, euphol effectiveness was not observed in a cAMP/PKA-induced mechanical hypersensitivity in mice. Single (1h prior) or repeated (twice daily during 3 or 13 days) treatments with euphol ameliorated painful peripheral neuropathy induced by paclitaxel and also the mechanical hypersensitivity induced by B16F10 melanoma cells injection, in mice. Additionally, in both inflammatory and neuropathic pain models, euphol consistently prevented PKCε up-regulation, as well as, inhibited the up-regulation of PKCε-activated intracellular pathways; namely nuclear factor-κB (NF-κB), cyclic AMP response element binding protein (CREB) and cyclo-oxygenase-2 (COX-2). The present results suggest the antinociceptive effect on persistent pain caused by euphol is likely dependent on the inhibition of pro-inflammatory mediators modulated by PKCε.
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Laboratório de Autoimunidade e Imunofarmacologia (LAIF), Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, SC, Brazil. Electronic address: rafaelcdutra@gmail.com.
authors.forename: R C
authors.initials: RC
authors.lastname: Dutra
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Bicca
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: G C
authors.initials: GC
authors.lastname: Segat
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: K A B S
authors.initials: KA
authors.lastname: Silva
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: E M
authors.initials: EM
authors.lastname: Motta
authors.affiliation: Kyolab Ltda, Rua Isaura Aparecida Oliveira Barbosa Terini, 231, Jardim Itapuã, 13273-105 Valinhos, SP, Brazil.
authors.forename: L F
authors.initials: LF
authors.lastname: Pianowski
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Departmento de Biotecnologia Farmaceutica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Costa
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: joao.calixto@cienp.org.br.
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D015232:Dinoprostone / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism; D007810:Lanosterol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D007810:Lanosterol; C062557:euphol; D051744:Protein Kinase C-epsilon; D015232:Dinoprostone
keywords: PKCε; euphol; inflammation; persistent pain