The activation of μ-opioid receptor potentiates LPS- induced NF-kB promoting an inflammatory phenotype in microglia

Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether mu-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 mu-opioid receptor, increases the DNA-binding activity of NF-kB via PKC epsilon, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKC epsilon signalling. The identification of morphine as a crucial upstream regulator of PKC epsilon-NF-kappa B signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine-PKC epsilon-NF-kappa B pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.