Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. An analysis of the mRNA/protein expression of CCR4 and its ligands was performed by qRT-PCR, microarray and/or Western blot methods. C021 (CCR4 antagonist), morphine and buprenorphine were injected intrathecally or intraperitoneally, and pain-related behavior was evaluated by the von Frey, cold plate and rotarod tests. We observed that on day 7 after STZ administration, the blood glucose level was increased, and as a consequence, hypersensitivity to tactile and thermal stimuli developed. In addition, we observed an increase in the mRNA level of CCL2 but not CCL17/CCL22. The microarray technique showed that the CCL2 protein level was also upregulated. In naive mice, the pronociceptive effect of intrathecally injected CCL2 was blocked by C021, suggesting that this chemokine acts through CCR4. Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids.

趋化因子信号传导与糖尿病神经病变的发病机制有关；然而，趋化因子 CC 基序受体 4 (CCR4) 的作用仍然未知。目的是检查 CCR4 在超敏反应发展中的功能和阿片类药物在糖尿病神经病变中的有效性。使用链脲佐菌素（STZ；200 mg/kg，腹膜内给药）诱导的糖尿病神经病变小鼠模型。通过 qRT-PCR、微阵列和/或蛋白质印迹方法对 CCR4 及其配体的 mRNA/蛋白质表达进行分析。鞘内或腹膜内注射CO21（CCR4拮抗剂）、吗啡和丁丙诺啡，并通过von Frey、冷板和旋转棒试验评估疼痛相关行为。我们观察到在 STZ 给药后第 7 天，血糖水平升高，因此，对触觉和热刺激产生超敏反应。此外，我们观察到 mRNA 水平的增加CCL2但不是CCL17/CCL22. 微阵列技术显示CCL2蛋白水平也上调。在幼稚的小鼠中，鞘内注射 CCL2 的前感受作用被 CO21 阻断，表明该趋化因子通过 CCR4 起作用。重要的是，我们的结果提供了第一个证据，即在糖尿病神经病变的小鼠模型中，单次鞘内和腹膜内注射 CO21 以剂量依赖性方式减少了神经性疼痛相关行为并改善了运动功能。此外，CO21 的单次鞘内和腹膜内注射都增强了吗啡和丁丙诺啡的有效性。这些结果表明，CCR4 的药理学调节可能是治疗糖尿病神经病变的良好潜在治疗靶点，并可能增强阿片类药物的有效性。