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

Abstract

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.

• Authors: Christina McDonnell, Sergi Leánez, Olga Pol
• Journal: PloS one (PLoS One) Vol. 12 Issue 7 Pg. e0180998 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28700700 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Blood Glucose
• Isothiocyanates
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Piperazines
• Receptors, Opioid, delta
• Sulfoxides
• 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
• Enkephalin, D-Penicillamine (2,5)-
• sulforaphane

Topics

• Animals
• Benzamides (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Blotting, Western
• Body Weight (drug effects, genetics, physiology)
• Diabetes Mellitus, Experimental (genetics, metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Diabetic Neuropathies (metabolism)
• Enkephalin, D-Penicillamine (2,5)- (pharmacology)
• Hyperalgesia (metabolism)
• Isothiocyanates (pharmacology)
• Male
• Mice
• NF-E2-Related Factor 2 (genetics, metabolism)
• Piperazines (pharmacology)
• Receptors, Opioid, delta (agonists, genetics, metabolism)
• Sulfoxides