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

Abstract

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.

Comparison of the Effects of Chemokine Receptors CXCR2 and CXCR3 Pharmacological Modulation in Neuropathic Pain Model—In Vivo and In Vitro Study

“…An intrathecal injection of most of these chemokines strongly induces mechanical and thermal hypersensitivity in naive animals [18,22,89,90]. Moreover, changes in their levels were noted in neuropathic pain states of different etiologies [8,13,19,22,91], consistent with our current results showing an increase in the levels of the CCL2, CCL3, CCL4, CCL6, CCL7, CXCL4, and CXCL9 mRNAs in the spinal cord and/or DRG on day 7 after sciatic nerve injury. Intrathecally administered antagonists of CXCR2 and CXCR3 were effective at reducing the levels of CCL2, CCL3, CCL6, CCL7, CXCL4, and/or CXCL9 in the spinal cord but not in the DRG.…”

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain

“…Given the involvement of chemokines in the development of both NP and opioidtolerance/hyperalgesia, several researchers have hypothesized that administration of chemokine-neutralizing antibodies or their receptor antagonists may simultaneously reduce pain-related behaviors and improve opioid efficacy in neuropathic conditions [246][247][248][249][250] (Figure 2). (A) Neuropathic pain conditions increase the production and release of a myriad of chemokines, whose binding to their specific receptors on neurons, astrocytes, and microglia decreases the nociceptive pain threshold and increases glial activation.…”

“…Given the involvement of chemokines in the development of both NP and opioid-tolerance/hyperalgesia, several researchers have hypothesized that administration of chemokine-neutralizing antibodies or their receptor antagonists may simultaneously reduce pain-related behaviors and improve opioid efficacy in neuropathic conditions [ 246 , 247 , 248 , 249 , 250 ] ( Figure 2 ).…”

“…Similar results were obtained with CCL2- and CCL7-neutralizing antibodies in chronic constriction injury (CCI) mice [ 252 ]. The role of the CCL2-CCL7/CCR2 pathway in hypersensitivity and opioid effects has been demonstrated by injecting two different CCR2 antagonists, RS504393 and cenicriviroc, into CCI rats [ 248 , 253 ]. RS504393, a selective CCR2-antagonist, reduced pain-related behaviors and enhanced analgesia of morphine and buprenorphine by increasing mRNA and protein levels of pronociceptive (i.e., IL-1β, IL-18, IL-6, and inducible nitric oxide synthase, iNOS) and antinociceptive (i.e., IL-1α) factors [ 253 ], without affecting spinal expression of CCL2 and CCL7 [ 254 ].…”

“…RS504393, a selective CCR2-antagonist, reduced pain-related behaviors and enhanced analgesia of morphine and buprenorphine by increasing mRNA and protein levels of pronociceptive (i.e., IL-1β, IL-18, IL-6, and inducible nitric oxide synthase, iNOS) and antinociceptive (i.e., IL-1α) factors [ 253 ], without affecting spinal expression of CCL2 and CCL7 [ 254 ]. Instead, cenicriviroc, a dual CCR2/CCR5 antagonist, alleviates mechanical/thermal hypersensitivity in CCI rats by decreasing the expression of CCL2, CCL7, and CCR2 in the spinal cord and CCR5 in the DRG and preventing the up-regulation of various pronociceptive mediators [ 248 , 254 ]. Cenicriviroc also improves the analgesic effect of morphine and buprenorphine, possibly by preventing the down-regulation of opioid receptors induced by the neuropathy in the DRG [ 248 ].…”