DataSheet_2_Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy.pdf

Clinical management of neuropathic pain is unsatisfactory, mainly due to its resistance to the effects of available analgesics, including opioids. Converging evidence indicates the functional interactions between chemokine and opioid receptors and their influence on nociceptive processes. Recent studies highlight that the CC chemokine receptors type 2 (CCR2) and 5 (CCR5) seem to be of particular interest. Therefore, in this study, we investigated the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behaviors, neuroimmune processes, and the efficacy of opioids in rats after chronic constriction injury (CCI) of the sciatic nerve. To define the mechanisms of action of cenicriviroc, we studied changes in the activation/influx of glial and immune cells and, simultaneously, the expression level of CCR2, CCR5, and important pronociceptive cytokines in the spinal cord and dorsal root ganglia (DRG). We demonstrated that repeated intrathecal injections of cenicriviroc, in a dose-dependent manner, alleviated hypersensitivity to mechanical and thermal stimuli in rats after sciatic nerve injury, as measured by von Frey and cold plate tests. Behavioral effects were associated with the beneficial impact of cenicriviroc on the activation/influx level of C1q/IBA-1-positive cells in the spinal cord and/or DRG and GFAP-positive cells in DRG. In parallel, administration of cenicriviroc decreased the expression of CCR2 in the spinal cord and CCR5 in DRG. Concomitantly, we observed that the level of important pronociceptive factors (e.g., IL-1beta, IL-6, IL-18, and CCL3) were increased in the lumbar spinal cord and/or DRG 7 days following injury, and cenicriviroc was able to prevent these changes. Additionally, repeated administration of this dual CCR2/CCR5 antagonist enhanced the analgesic effects of morphine and buprenorphine in neuropathic rats, which can be associated with the ability of cenicriviroc to prevent nerve injury-induced downregulation of all opioid receptors at the DRG level. Overall, our results suggest that pharmacological modulation based on the simultaneous blockade of CCR2 and CCR5 may serve as an innovative strategy for the treatment of neuropathic pain, as well as in combination with opioids.

神经病理性疼痛的临床治疗效果欠佳，主要原因在于其对包括阿片类药物在内的现有镇痛药产生耐药性。汇聚性证据表明，趋化因子与阿片类受体之间存在功能相互作用，并可对伤害感受过程产生影响。近期研究凸显出CC趋化因子受体2型（CCR2）与5型（CCR5）尤为值得关注。因此，本研究针对坐骨神经慢性压迫损伤（CCI）后的大鼠，探究了双重CCR2/CCR5拮抗剂西尼瑞韦（cenicriviroc）对疼痛相关行为、神经免疫过程以及阿片类药物疗效的影响。为明确西尼瑞韦的作用机制，我们分析了脊髓与背根神经节（DRG）中神经胶质细胞与免疫细胞的激活/浸润情况，同时检测了CCR2、CCR5以及重要致痛性细胞因子的表达水平。研究结果显示，经鞘内反复注射西尼瑞韦后，可通过剂量依赖的方式缓解坐骨神经损伤大鼠对机械刺激与热刺激的痛觉超敏反应，该结果通过冯弗雷试验与冷板试验得以验证。行为学改善与西尼瑞韦对脊髓及/或背根神经节中补体C1q/离子钙结合衔接分子1（IBA-1）阳性细胞，以及背根神经节中胶质纤维酸性蛋白（GFAP）阳性细胞的激活/浸润水平的有益调控作用相关。与此同时，西尼瑞韦给药可降低脊髓中CCR2的表达，以及背根神经节中CCR5的表达。我们同时观察到，损伤7天后，大鼠腰段脊髓及/或背根神经节内的重要致痛因子（如IL-1β、IL-6、IL-18及CC趋化因子配体3（CCL3））水平升高，而西尼瑞韦可阻断此类变化。此外，对神经病理性疼痛大鼠反复给予该双重CCR2/CCR5拮抗剂，可增强吗啡与丁丙诺啡的镇痛效果，这一现象可能与西尼瑞韦能够阻止神经损伤诱导的背根神经节处所有阿片类受体的表达下调有关。综上，本研究结果表明，同时阻断CCR2与CCR5的药理学调控策略，或可成为治疗神经病理性疼痛的创新方案，亦可与阿片类药物联合应用。