Abstract <p>Mounting evidence implicates that chemokine receptors type 2 and 5 play a pivotal role in neuropathic pain. Here, we report for the first time that cenicriviroc, a dual CCR2/CCR5 antagonist, exerts strong, long-lasting, and morphine-potentiating effects in a mouse model of chronic constriction injury (CCI) to the sciatic nerve. The analgesic effect of cenicriviroc was comparable to that of morphine in the initial phase of neuropathy (Day 3) and, rewardingly, superior to the effect of morphine on Days 8 and 16 of twice-daily intraperitoneal administration. Moreover, on Day 16, tolerance to the analgesic effect of morphine was less pronounced in the group that received cenicriviroc before every morphine injection. Immunofluorescence analysis confirmed that CCR2 colocalizes with microglia/macrophages. Luminex analyses revealed time-dependent CCI-induced spinal increases in several kinases (p38, ERK, JNK, Akt), transcription factors (NF-κB, STAT3), and cytokines (IL-10, IL-1β, TNFα, CCL2/3/5). No less importantly, there was a pronounced elevation of pronociceptive mediators (TNFα, IL-1β, CCL2/3/4/5, pERK, and pNF-κB) following prolonged morphine administration over 16 days; all these factors can potentially contribute to the emergence of tolerance and tactile hypersensitivity. In contrast to morphine, cenicriviroc on Day 3 increased the level of antinociceptive IL-10, while decreasing pERK. Furthermore, on Day 8, cenicriviroc increased the level of Akt/STAT3, and decreased pp38/pERK and pronociceptive CCL2/3/5. The obtained results indicate that simultaneous targeting of CCR2/5 by cenicriviroc may have great potential for neuropathic pain therapies, especially since the drug is already in clinical trials for other conditions.</p> Graphical Abstract <p></p>