Diabetic neuropathic pain is a frequent complication of diabetic neuropathy. The specific manifestations of diabetic neuropathic pain include spontaneous pain and hyperalgesia, which seriously affect the quality of life of patients. Previous publications have shown that H₂S has both pro-nociceptive and anti-nociceptive effects. This present investigation aimed to examine the anti-nociceptive effect of H₂S on diabetic neuropathic pain. We established a diabetic neuropathic pain animal model with high-glucose, high-fat diet, and STZ, then treated rats with different concentrations of H₂S and inhibitors of NOS, sGC, PKG, and opioid receptors. The mechanical allodynia and thermal hyperalgesia of rats were measured to assess the anti-nociceptive effects of H₂S. The mRNA and protein expression of NOS and PKG1 were measured to explore their roles in the anti-nociceptive action of H₂S. The results revealed that inhalation of H₂S gas had anti-nociceptive effect in diabetic neuropathic pain model rats without affecting the blood glucose level and body mass. It increased the mRNA and protein level of nNOS, and the inhibitor of nNOS, 7-NI, abolished the anti-nociceptive effect of H₂S. Furthermore, inhibitors of sGC and PKG could also abolish the anti-nociceptive effect of H₂S. The expression of PKG1 was found to be increased by H₂S, which was reversed by the inhibitors of nNOS, sGC, and PKG. Finally, CTOP, a μ-opioid receptor antagonist, abolished the anti-nociceptive effect of H₂S, indicating that the μ-opioid receptor plays a role in the anti-nociceptive effect of H₂S. In conclusion, the findings of this investigation suggest that hydrogen sulfide may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor.

Impact statement

There are currently approximately 425 million diabetic patients worldwide, of which approximately 90% of patients with diabetes suffer from neuropathy. Diabetic neuropathic pain (DNP) is a common complication of diabetic neuropathy. Nearly half of the patients hospitalized with diabetes have pain symptoms or symptoms related to neurological injury, and the incidence increases with age and diabetic duration. Anti-DNP analgesics have either limited therapeutic effects or serious side effects or lack of clinical trials, which has limited their application. Physiopathological mechanisms and treatment of DNP remain a significant challenge. The present confirmed that inhalation of H₂S may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. It provides us the animal study foundation for the application of H₂S on the treatment of DNP and clarifies some target molecules in the pain modulation of DNP.

中文翻译：

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硫化氢通过NO / cGMP / PKG途径和μ阿片受体减轻糖尿病性神经痛。

糖尿病性神经性疼痛是糖尿病性神经病的常见并发症。糖尿病性神经性疼痛的具体表现包括自发性疼痛和痛觉过敏，严重影响患者的生活质量。先前的出版物已经表明，H ₂ S具有伤害感受和伤害感受的作用。本研究旨在检查H ₂ S对糖尿病性神经性疼痛的镇痛作用。我们建立了具有高糖，高脂饮食和STZ的糖尿病性神经性疼痛动物模型，然后用不同浓度的H ₂ S以及NOS，sGC，PKG和阿片受体的抑制剂治疗了大鼠。测量大鼠的机械性异常性疼痛和热痛觉过敏，以评估H的抗伤害感受作用₂ S. mRNA和NOS和PKG1的蛋白质表达进行测定，以探索在H的抗感受伤害作用的角色₂ S.结果显示H的该吸入₂的天然气过在糖尿病性神经性疼痛模型大鼠的抗感受伤害作用而不影响血糖水平和体重。它增加了nNOS的mRNA和蛋白水平，nNOS抑制剂7-NI消除了H ₂ S的抗伤害感受作用。此外，sGC和PKG抑制剂也可消除H ₂ S的抗伤害感受作用。发现H ₂增加PKG1的表达。S，被nNOS，sGC和PKG的抑制剂逆转。最后，CTOP，一个μ阿片受体拮抗剂，废除H的抗感受伤害的效果₂ S，这表明μ阿片受体在H的抗感受伤害作用的角色₂ S.总之，在此发现研究表明，硫化氢可通过NO / cGMP / PKG途径和μ阿片受体减轻糖尿病性神经痛。

影响陈述

目前，全世界约有4.25亿糖尿病患者，其中约90％的糖尿病患者患有神经病。糖尿病性神经性疼痛（DNP）是糖尿病性神经病的常见并发症。住院的糖尿病患者中几乎有一半患有疼痛症状或与神经系统损伤有关的症状，并且发病率随年龄和糖尿病持续时间的增加而增加。抗DNP镇痛药要么疗效有限，要么副作用严重，或者缺乏临床试验，这限制了它们的应用。DNP的生理病理机制和治疗仍然是一项重大挑战。目前证实吸入H ₂S可以通过NO / cGMP / PKG途径和μ阿片受体减轻糖尿病性神经性疼痛。它为H ₂ S在DNP的治疗中的应用提供了动物研究基础，并阐明了DNP在痛觉调节中的一些靶分子。