Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results: I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 (Trpa1-/- ), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1-/- mice. Conclusion: This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.

中文翻译：

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在1型糖尿病小鼠模型中，Nav1.7和甲基乙二醛介导的TRPA1激活在瘙痒和痛觉过敏中的作用。

甲基乙二醛（MGO）是一种内源性反应性羰基化合物，在糖尿病性神经病的发病机理中起关键作用。这项研究的目的是研究MGO在糖尿病性瘙痒和痛觉过敏中的作用，这是与糖尿病性神经病相关的两个常见症状。方法：在腹膜内（ip）注射链脲佐菌素（STZ）诱导的初生小鼠或糖尿病小鼠中，皮内注射（id）MGO后，对S痒行为，机械性瘙痒（变态反应）和热痛觉过敏进行定量。行为测试，膜片钳记录，转基因小鼠和基因表达分析用于研究小鼠糖尿病性瘙痒和痛觉过敏的潜在机制。结果：在正常小鼠中，Id注射MGO会引起剂量依赖性的ing抓。MGO的直接激活瞬态受体电位锚蛋白1（TRPA1）诱导在背根神经节（DRG）神经元或表达TRPA1的HEK293细胞中的内向电流和钙内流。在STZ诱导的糖尿病小鼠中出现了机械性瘙痒，但不是自发性瘙痒。Trpa1（Trpa1-/-）的遗传消融，TRPA1和Nav1.7的药理学阻滞剂，抗氧化剂和MGO或在STZ诱导的糖尿病小鼠中引起的瘙痒被废止。通过鞘内注射MGO或在STZ诱导的糖尿病小鼠中诱导热痛觉过敏，这种情况已被MGO清道夫，鞘内注射TRPA1阻滞剂和在Trpa1-/-小鼠中消除。结论：这项研究揭示了Nav1。7和MGO介导的TRPA1激活在1型糖尿病小鼠模型的瘙痒和痛觉过敏中起关键作用。因此，我们提供了一种治疗糖尿病性神经病引起的瘙痒和痛觉过敏的新型潜在治疗策略。