PDF(Pubmed)
Abstract：
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 Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 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.
摘要：
趋化因子受体2和5的配体（分别为CCR2和CCR5）与神经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患者的超敏反应中的作用.此外,我们分析了cenicriviroc（CVC）的镇痛作用，CCR2/CCR5双重拮抗剂，以及它对吗啡有效性的影响。越来越多的实验研究表明,就其镇痛作用而言,与共同施用单独的药效团相比,靶向多于一个分子靶标是有利的。使用双功能化合物的优点是它们以相同的剂量同时接触两种受体，积极影响他们的药代动力学和药效学，从而导致改善镇痛。用链脲佐菌素（STZ，200mg/kg,i.p.)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天出现机械和热超敏反应。在雄性小鼠中,我们观察到Ccl2，Ccl5和Ccl7的mRNA水平增加，而在雌性小鼠中，我们观察到Ccl8和Ccl12水平的额外增加。我们首次证明，单次服用cenicriviroc可在雄性和雌性小鼠中缓解疼痛的程度相似。此外，cenicriviroc与吗啡的反复联合给药延迟了阿片类药物耐受性的发展，虽然通过单独反复服用cenicriviroc可以实现最佳和最长的镇痛效果，减少STZ暴露小鼠的疼痛超敏反应，和吗啡不同,直到治疗的第15天未观察到对CVC的镇痛作用的耐受性。基于这些结果,我们认为,针对CCR2和CCR5的CVC是糖尿病神经病变患者新型疼痛治疗的有效治疗选择.
