Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pain Pharmacology, 12 Smetna Street, 31-343, Krakow, Poland.
Department of Pain Research and Treatment, Chair of Anesthesiology and Intensive Therapy, Jagiellonian University Medical College, Krakow, Poland.
Eur J Pharmacol. 2020 Aug 5;880:173166. doi: 10.1016/j.ejphar.2020.173166. Epub 2020 May 11.
Neuropathic pain is a chronic condition which significantly reduces the quality of life and serious clinical issue that is in general resistant to available therapies. Therefore looking for new analgesics is still critical issue. Recent, studies have indicated that chemokine signaling pathways are crucial for the development of neuropathy; however, the role of CC chemokine receptor 4 (CCR4) in this process has not yet been studied. Therefore, the aim of our research was to investigate the influence of C021 (a CCR4 antagonist) and CCR4 CC chemokine ligands 17 and 22 (CCL17 and CCL22) on the development of hypersensitivity and the effectiveness of morphine induced analgesia in naive animals and/or animals exposed to chronic constriction injury (CCI) of the sciatic nerve. Firstly, we demonstrated that the intrathecal administration of CCL17 and CCL22 induced pain-related behavior in naive mice. Secondly, we revealed that the intrathecal injection of C021 significantly reduced CCI-induced hypersensitivity after nerve injury. In parallel, C021 reduced microglia/macrophages activation and the level of some pronociceptive interleukins (IL-1beta; IL-18) in the spinal cord 8 days after CCI. Moreover, C021 not only attenuated mechanical and thermal hypersensitivity but also enhanced the analgesic properties of morphine. Our research indicates that CCR4 ligands might be important factors in the early stages of neuropathy, when we observe intense microglia/macrophages activation. Moreover, pharmacological blockade of CCR4 may serve as a potential new target for better understanding the mechanisms of neuropathic pain development.
神经病理性疼痛是一种慢性疾病，会显著降低生活质量，是一种普遍对现有治疗方法有抗性的严重临床问题。因此，寻找新的镇痛药仍然是一个关键问题。最近的研究表明，趋化因子信号通路对于神经病的发展至关重要；然而，CC 趋化因子受体 4（CCR4）在这个过程中的作用尚未得到研究。因此，我们的研究目的是调查 C021（CCR4 拮抗剂）和 CC 趋化因子配体 17 和 22（CCL17 和 CCL22）对敏感性发展和吗啡诱导的镇痛效果在未受伤动物和/或暴露于坐骨神经慢性缩窄性损伤（CCI）的动物中的影响。首先，我们证明鞘内给予 CCL17 和 CCL22 在未受伤的小鼠中引起与疼痛相关的行为。其次，我们揭示鞘内注射 C021 可显著减轻神经损伤后的 CCI 诱导的过敏反应。同时，C021 减少了 CCI 后 8 天脊髓中小胶质细胞/巨噬细胞的激活和一些致痛性白细胞介素（IL-1β；IL-18）的水平。此外，C021 不仅减轻了机械和热过敏反应，而且增强了吗啡的镇痛作用。我们的研究表明，CCR4 配体可能是神经病早期的重要因素，此时我们观察到强烈的小胶质细胞/巨噬细胞激活。此外，CCR4 的药理学阻断可能成为更好地理解神经病理性疼痛发展机制的潜在新靶点。
