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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01332


Pablo Ferreira1, Alejandro Redondo1, Gabriela Riego1, Sergi Leánez1 and  Olga Pol1*
  • 1Grup de Neurofarmacologia Molecular, Sant Pau Institute for Biomedical Research, Spain

Chronic neuropathic pain is associated with anxiety- and depressive-like disorders. Its treatment remains a serious clinical problem due to the lack of efficacy of the available therapeutic modalities. We investigated if the activation of the transcription factor Nrf2 could modulate the nociceptive and emotional disorders associated with persistent neuropathic pain and potentiated the analgesic activity of morphine. The possible mechanisms implicated in these effects have been also evaluated. Therefore, in C57BL/6 mice with neuropathic pain induced by the chronic constriction of the sciatic nerve (CCI), we assessed the antinociceptive, anxiolytic and anti-depressant effects of the repeated intraperitoneal administration of a Nrf2 inducer, sulforaphane (SFN), and the effects of this treatment on the local antinociceptive actions of morphine. The protein levels of Nrf2, heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), CD11b/c (a microglial activator marker), mitogen-activated protein kinases (MAPK) and μ opioid receptors (MOR) in the spinal cord, prefrontal cortex and hippocampus from mice, at 28 days after CCI, were also evaluated. Our results showed that the repeated administration of SFN besides inhibiting nociceptive responses induced by sciatic nerve injury also diminished the anxiety- and depressive-like behaviors associated with persistent neuropathic pain. Moreover, SFN treatment normalized oxidative stress by inducing Nrf2/HO-1 signaling, reduced microglial activation and JNK, ERK1/2, p-38 phosphorylation induced by sciatic nerve injury in the spinal cord and/or hippocampus and prefrontal cortex. Interestingly, treatment with SFN also potentiated the antiallodynic effects of morphine in sciatic nerve-injured mice by regularizing the down regulation of MOR in the spinal cord and/or hippocampus. This study suggested that treatment with SFN might be an interesting approach for the management of persistent neuropathic pain and comorbidities associated as well as to improve the analgesic actions of morphine.

Keywords: Analgesia, Anxiety, Depression, Nrf2 (nuclear factor erythroid 2-related factor 2), opioid, Chronic Pain

Received: 28 Aug 2018; Accepted: 29 Oct 2018.

Edited by:

Águeda González Rodríguez, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Spain

Reviewed by:

Stefania Ceruti, Università degli Studi di Milano, Italy
Luigi Brunetti, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy  

Copyright: © 2018 Ferreira, Redondo, Riego, Leánez and Pol. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Olga Pol, Sant Pau Institute for Biomedical Research, Grup de Neurofarmacologia Molecular, Barcelona, Catalonia, Spain,