Department of Endocrine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China.
Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China.
Brain Res. 2021 Dec 1;1772:147663. doi: 10.1016/j.brainres.2021.147663. Epub 2021 Sep 20.
Neuropathic pain is a common complication of diabetes mellitus with poorly relieved by conventional analgesics. Metformin, a first-line drug for type 2 diabetes, reduces blood glucose by activating adenosine monophosphate protein kinase (AMPK) signalling system. However, the effect of Metformin on diabetic neuropathic pain is still unknown. In the present study, we showed that Metformin was capable of attenuating diabetes induced mechanical allodynia, and the analgesia effect could be blocked by Compound C (an AMPK inhibitor). Importantly, Metformin enhanced the phosphorylation level of AMPK in L4-6 DRGs of diabetic rats but not affect the expression of total AMPK. Intrathecal injection of AICAR (an AMPK agonist) could activate AMPK and alleviate the mechanical allodynia of diabetic rats. Additionally, phosphorylated AMPK and NF-κB was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-κB in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-κB expression in L4-6 DRGs of diabetic rats, but the decrease was blocked by Compound C. In conclusion, Metformin alleviates diabetic mechanical allodynia via activation of AMPK signaling pathway in L4-6 DRGs of diabetic rats, which might be mediated by the downregulation of NF-κB, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain.
神经病理性疼痛是糖尿病的常见并发症，常规镇痛药物对此缓解效果不佳。二甲双胍是治疗 2 型糖尿病的一线药物，通过激活单磷酸腺苷蛋白激酶（AMPK）信号系统来降低血糖。然而，二甲双胍对糖尿病性神经病理性疼痛的影响尚不清楚。在本研究中，我们表明二甲双胍能够减轻糖尿病引起的机械性痛觉过敏，而这种镇痛作用可以被 Compound C（一种 AMPK 抑制剂）阻断。重要的是，二甲双胍增强了糖尿病大鼠 L4-6 背根神经节中 AMPK 的磷酸化水平，但不影响总 AMPK 的表达。鞘内注射 AICAR（一种 AMPK 激动剂）可以激活 AMPK，减轻糖尿病大鼠的机械性痛觉过敏。此外，磷酸化的 AMPK 和 NF-κB 在 L4-6 背根神经节的中小神经元中存在共定位。有趣的是，当 AMPK 被 AICAR 激活时，糖尿病大鼠中 NF-κB 的调节明显减少。值得注意的是，二甲双胍可以降低糖尿病大鼠 L4-6 背根神经节中 NF-κB 的表达，但 Compound C 可阻断这一作用。总之，二甲双胍通过激活糖尿病大鼠 L4-6 背根神经节中的 AMPK 信号通路缓解糖尿病性机械性痛觉过敏，这可能是通过下调 NF-κB 介导的，这为二甲双胍成为治疗糖尿病性神经病理性疼痛的潜在药物提供了一定的依据。
