Department of Pain Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland.
Int J Mol Sci. 2024 Jul 5;25(13):7410. doi: 10.3390/ijms25137410.
The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of , , and , while in female mice, we observed additional increases in and levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.
趋化因子受体 2 和 5（CCR2 和 CCR5，分别）的配体与神经病理性疼痛发展的病理机制有关，但它们在痛性糖尿病神经病变中的作用尚不清楚。因此，我们的研究目的是研究这些因素在糖尿病伴发的高敏性中的作用。此外，我们还分析了双重 CCR2/CCR5 拮抗剂西尼立诺（CVC）的镇痛作用及其对吗啡疗效的影响。越来越多的实验研究表明，与单独使用药效团相比，针对多个分子靶点具有优势，因为其镇痛效果更好。使用双功能化合物的优势在于，它们以相同的剂量同时获得对两个受体的作用，从而积极影响其药代动力学和药效学，从而导致镇痛效果改善。实验在雄性和雌性瑞士白化小鼠中进行，使用链脲佐菌素（STZ，200 mg/kg，ip）糖尿病神经病变模型。我们发现，血糖水平升高，STZ 给药后第 7 天出现机械和热高敏性。在雄性小鼠中，我们观察到 、 和 的 mRNA 水平增加，而在雌性小鼠中，我们观察到 和 的水平进一步增加。我们首次证明，单次给予西尼立诺在雄性和雌性小鼠中均能达到相似程度的镇痛效果。此外，重复给予西尼立诺与吗啡共同给药可延迟阿片类药物耐受的发展，而重复给予西尼立诺本身可获得最佳和最长时间的镇痛效果，可减轻 STZ 暴露小鼠的疼痛高敏性，并且与吗啡不同，直到治疗第 15 天，才观察到对 CVC 镇痛作用的耐受。基于这些结果，我们建议使用 CVC 靶向 CCR2 和 CCR5 是治疗糖尿病神经病变患者新型疼痛的有效治疗选择。
