Background and aims: Unsatisfactory management of chronic pain significantly impairs patients' quality of life. Recent studies focused on the search for new analgesics indicated the key role of CCR2 and CCR5 chemokine receptors in neuropathy. Therefore, the aim was to investigate the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behavior and morphine effectiveness in neuropathic pain. To define mechanisms underlying observed effects, we studied changes in the level of microglial activation and important pronociceptive cytokines.

Methods: Wistar rats were implanted with intrathecal catheters. Afterwards, chronic constriction injury of sciatic nerve was performed. Cenicriviroc (CVC) was administered intrathecally, preemptively, and then once per day for 7 days. The last day rats received a single dose of morphine. Pain-related behaviors were measured using von Frey and cold plate test. Biochemical analysis was performed using RT-qPCR. 

Results: Our studies showed that CVC attenuated mechanical and thermal hypersensitivity and enhanced morphine-induced analgesia in a rat neuropathic pain model. Simultaneously, CVC diminished the activation of microglia/macrophages and prevented the CCI-induced mRNA upregulation of IL-1beta, NOS2, CCL2, CCL3 and CCL7 in the spinal cord and/or dorsal root ganglia. However, do not influence the level of IL-18. 

Conclusion: We demonstrated that beneficial effects of CVC result from reduction in the level of important pronociceptive factors. It suggests that pharmacological modulation of CCR2/CCR5 may serve as an innovative strategy for neuropathic pain treatment. 

Acknowledgments: National Science Centre grants: OPUS-2016/21/B/NZ4/00128, PRELUDIUM-2018/29/N/NZ7/00287 and statutory funds of Institute of Pharmacology, PAS.

THE DUAL CCR2/CCR5 ANTAGONIST, CENICRIVIROC, ATTENUATED NEUROPATHIC PAIN-RELATED BEHAVIOR AND ENHANCED MORPHINE EFFECTIVENESS