McDonnell Christina, Leánez Sergi, Pol Olga
Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain.
Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
PLoS One. 2017 Jul 10;12(7):e0180998. doi: 10.1371/journal.pone.0180998. eCollection 2017.
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.
血红素加氧酶1（HO-1）参与1型糖尿病中阿片类药物抗伤害感受作用的调节已得到证实，但转录因子Nrf2在2型糖尿病疼痛性神经病变的调节以及δ-阿片受体（DOR）的作用和表达中的作用尚未得到研究。在雄性BKS.Cg-m+/+Leprdb/J（db/db）小鼠中，评估了单独给予Nrf2转录因子激活剂萝卜硫素（SFN）以及与两种DOR激动剂，[d-Pen(2),d-Pen(5)]-脑啡肽（DPDPE）和(+)-4-[(αR)-α-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基]-N,N-二乙苯甲酰胺（SNC-80）联合使用所产生的抗痛觉过敏作用。还评估了SFN对db/db小鼠血糖水平、体重以及坐骨神经中Nrf2、HO-1、NAD(P)H：醌氧化还原酶1（NQO1）、丝裂原活化蛋白激酶（JNK）和DOR蛋白水平的影响。这项研究表明，给予SFN可剂量依赖性地逆转机械性痛觉过敏，降低与2型糖尿病相关的高血糖和体重增加，并显著增强DPDPE和SNC-80对db/db小鼠的抗痛觉过敏作用。这种治疗使db/db小鼠中Nrf2和NQO1的下调恢复正常，并提高了HO-1的蛋白水平。此外，给予SFN还抑制了糖尿病小鼠坐骨神经中JNK的磷酸化和DOR的下调。我们的数据表明，SFN治疗可有效逆转db/db小鼠的机械性痛觉过敏并增强DOR的抗伤害感受作用，其作用可能是通过激活Nrf2信号传导、降低高血糖、抑制JNK磷酸化以及避免这些动物坐骨神经中DOR下调来介导的。这些结果表明，SFN单独和/或与DOR激动剂联合使用，是治疗小鼠2型糖尿病相关疼痛性糖尿病神经病变的有趣方法。
