The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts potent antioxidative and anti-inflammatory effects; however, its participation in the modulation of chronic inflammatory
pain and on the antinociceptive effects of μ-
opioid receptor (MOR) agonists has not been evaluated. We investigated whether the induction of Nrf2 could alleviate chronic inflammatory
pain and augment the
analgesic effects of
morphine and mechanisms implicated. In male C57BL/6 mice with inflammatory
pain induced by complete
Freund's adjuvant (CFA) subplantarly administered, we assessed: 1) antinociceptive actions of the administration of 5 and 10 mg/kg of a Nrf2 activator,
sulforaphane (SFN); and 2) effects of SFN on the antinociceptive actions of
morphine and on
protein levels of Nrf2,
heme oxygenase 1 (HO-1), and
NAD(P)H:
quinone oxidoreductase 1 (NQO1)
enzymes, microglial activation and
inducible nitric oxide synthase (NOS2) overexpression, as well as on
mitogen-activated protein kinase (MAPK) and MOR expression in the spinal cord and paw of animals with inflammatory
pain. Results showed that treatment with SFN inhibited
allodynia and
hyperalgesia induced by CFA and increased the local antinociceptive actions of
morphine. This treatment also augmented the expression of Nrf2, HO-1, NQO1, and MOR, and inhibited NOS2 and CD11b/c overexpression and MAPK phosphorylation induced by
inflammation. Thus, this study shows that the induction of Nrf2 might inhibit inflammatory
pain and enhance the
analgesic effects of
morphine by inhibiting oxidative stress and inflammatory responses induced by peripheral
inflammation. This study suggests the administration of SFN alone and in combination with
morphine are potential new ways of treating chronic inflammatory
pain.