Treatment with Sulforaphane Produces Antinociception and Improves Morphine Effects during Inflammatory Pain in Mice

Abstract

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 -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.

Role of Keap1-Nrf2 Signaling in Anhedonia Symptoms in a Rat Model of Chronic Neuropathic Pain: Improvement With Sulforaphane

“…In this study, we found that SNI rats with anhedonia-like phenotype had lower tissue Keap1 and Nrf2 levels in the spinal cord than those in sham-operated rats. Given the role of Keap1-Nrf2 signaling in pain ( Kim et al, 2010 ; Redondo et al, 2017 ), reduced Keap1-Nrf2 signaling in the spinal cord may play a role in neuropathic pain, although not in anhedonia-like phenotypes.…”

“…Furthermore, dietary intake of glucoraphanin during juvenile and adolescent stages confers resilience to chronic social defeat stress in adulthood ( Yao et al, 2016b ). Previous reports have shown that intrathecal administration of SFN attenuated mechanical allodynia and thermal hyperalgesia in spinal nerve transfection-injured mice ( Kim et al, 2010 ), and that SFN inhibited complete Freund’s adjuvant-induced allodynia and hyperalgesia ( Redondo et al, 2017 ). Taken together, it is likely that SFN is a potential natural compound for treating comorbid pain and depression.…”

Sulforaphane Inhibited the Nociceptive Responses, Anxiety- and Depressive-Like Behaviors Associated With Neuropathic Pain and Improved the Anti-allodynic Effects of Morphine in Mice

“…In other experiments, the evaluation of the effects produced by the intraperitoneal injection of 10 mg/kg of SFN combined with 50 μg of morphine, subplantarly administered, on the allodynia and hyperalgesia induced by CCI was carried out at 3 h after SFN administration ( n = 6 animals per group). The doses of SFN and morphine were selected in accordance to other studies ( Redondo et al, 2017 ; Wang and Wang, 2017 ).…”

“…SFN has been also proven in humans demonstrating that this treatment improves the glucose levels in patients with type 2 diabetes ( Axelsson et al, 2017 ), has beneficial clinical effects against autism disorders ( Singh et al, 2014 ) and gastrointestinal diseases ( Yanaka, 2018 ). Recent studies also showed the analgesic properties of SFN in several animal pain models and its capacity to potentiate the antinociceptive effects of opioids in animals with inflammatory pain or diabetic neuropathy ( McDonnell et al, 2017 ; Redondo et al, 2017 ). Taking account the lower efficacy of opioids, particularly μ-opioid receptor (MOR) agonists in the management of neuropathic pain ( Hervera et al, 2013 ; Zychowska et al, 2013 ; Popiolek-Barczyk and Mika, 2016 ), the investigation of new tools for increasing their analgesic efficacy is a priority in the current pain research.…”

“…The transcription factor Nrf2 also modulates inflammatory responses of the organism by inhibiting the synthesis of various proinflammatory mediators, such as the inducible nitric oxide synthase (NOS2), cyclooxygenase-2, interleukin (IL)-1α, IL-6, and mitogen-activated protein kinase (MAPK), among others ( Kim et al, 2009 ; Davidson et al, 2013 ; Kobayashi et al, 2016 ). Furthermore, diverse studies revealed that the stimulation of Nrf2 reduced acute and inflammatory pain as well as neuropathic pain accompanying to diabetes ( Negi et al, 2011 ; Di et al, 2016 ; McDonnell et al, 2017 ; Redondo et al, 2017 ), but the potential inhibitory role played by this transcription factor on the allodynia and hyperalgesia caused by nerve injury-induced persistent neuropathic pain has not been evaluated.…”