Research Article: The induction of the transcription factor Nrf2 enhances the antinociceptive effects of delta-opioid receptors in diabetic mice

Date Published: July 10, 2017

Publisher: Public Library of Science

Author(s): Christina McDonnell, Sergi Leánez, Olga Pol, Andrea Caporali.


The involvement of heme oxygenase 1 (HO-1) in the modulation of the antinociceptive effects of opioids in type 1 diabetes has been demonstrated but the role played by the transcription factor Nrf2 in the regulation of painful neuropathy and in the effects and expression of δ-opioid receptors (DOR) in type 2 diabetes, has not been studied. In male BKS.Cg-m+/+Leprdb/J (db/db) mice, the anti-allodynic effects produced by a Nrf2 transcription factor activator, sulforaphane (SFN) administered alone and combined with two DOR agonists, [d-Pen(2),d-Pen(5)]-Enkephalin (DPDPE) and (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide (SNC-80), were evaluated. The effects of SFN on glucose levels and body weight as well as on the proteins levels of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1), MAPKs (JNK) and DOR in sciatic nerve from db/db mice were also assessed. This study showed that the administration of SFN dose dependently reversed mechanical allodynia, reduced hyperglycemia and body weight gain associated to type 2 diabetes and significantly increased the anti-allodynic effects of DPDPE and SNC-80 in db/db mice. This treatment normalized the down regulation of Nrf2 and NQO1 and enhanced the protein levels of HO-1 in db/db mice. Moreover, the administration of SFN also inhibited the JNK phosphorylation and DOR down-regulation in the sciatic nerve of diabetic mice. Our data indicated that SFN treatment is effective in reversing mechanical allodynia and enhancing DOR antinociceptive effects in db/db mice which effects might be mediated by activating Nrf2 signaling, reducing hyperglycemia, inhibiting JNK phosphorylation and avoiding DOR down-regulation in the sciatic nerve of these animals. These results propose SFN, alone and/or combined with DOR agonists, as interesting approaches for the treatment of painful diabetic neuropathy associated to type 2 diabetes in mice.

Partial Text

Diabetic neuropathy and oxidative stress are two of the major complications associated with the development of diabetes that affects between 40–50% of people who suffer from this disorder. The clinical characteristics of diabetic neuropathy ranging from sensory deficit to allodynia (painful reaction to innocuous stimuli), and an increased sensitivity to painful stimulus [1, 2]. However, despite being one of the major symptoms of this metabolic disorder, diabetic neuropathy remains difficult to treat which highlight the importance of finding new therapeutic strategies.

In this study, we demonstrated that the intraperitoneal administration of SFN completely reversed the mechanical allodynia and reduced glucose levels and body weight gain in a mouse model of type 2 diabetes. In addition, the decreased sciatic nerve protein levels of Nrf2 and NQO1 associated to diabetes were reversed by SFN treatment, which also enhanced the expression of HO-1 and reduced the phosphorylation of JNK in the sciatic nerve of diabetic mice. The results of this study also indicated that the administration of each of the two DOR agonists, DPDPE and SNC-80, dose dependently inhibited the mechanical allodynia in db/db mice and treatment with SFN increased its anti-allodynic effects by normalizing the down regulation of DOR in the sciatic nerve of diabetic mice.




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