title: The activation of μ-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia.
abstract: Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether μ-opioid receptor affects proinflammatory signalling through the activation of NF-kB in microglia. The novelty of the described research is that a low dose of morphine, exerting its effects via the μ-opioid receptor, increases the DNA-binding activity of NF-kB via PKCε, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKCε signalling. The identification of morphine as a crucial upstream regulator of PKCε-NF-κB signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine-PKCε-NF-κB pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bencivenni
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Fazzi
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004361:Drug Tolerance / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; C498144:Rela protein, mouse; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D009020:Morphine; D051744:Protein Kinase C-epsilon
keywords: Akt; PKCε; mitogen-activated protein kinases; neuroinflammation; nuclear factor-kB; opioid receptor