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

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.