CCR4 Antagonist (C021) Administration Diminishes Hypersensitivity and Enhances the Analgesic Potency of Morphine and Buprenorphine in a Mouse Model of Neuropathic Pain

Abstract

Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of CCL17 and CCL22 remained unchanged in contrast to that of CCL2 , which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy.

Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice

“…In the present study, our western blot results demonstrated that rCCL17 administration increased the expression of CCR4 but pretreatment with C021 decreased the expression of CCR4. Previous study showed intraperitoneal administration of C021 diminished the levels of CCL17 [ 42 ]. In the present study, we observed that C021 reduced the expression of CCR4.…”

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

“…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 ]. In addition, Bogacka et al [ 255 ] reported that CCL2 can exert its pronociceptive effect by binding to CCR4. Thus, blocking CCR4 with its antagonist, C021, may reduce the development of mechanical and thermal hypersensitivity, improve the efficacy of morphine and buprenorphine, and stop the development of morphine tolerance in CCI mice [ 255 ].…”

“…In addition, Bogacka et al [ 255 ] reported that CCL2 can exert its pronociceptive effect by binding to CCR4. Thus, blocking CCR4 with its antagonist, C021, may reduce the development of mechanical and thermal hypersensitivity, improve the efficacy of morphine and buprenorphine, and stop the development of morphine tolerance in CCI mice [ 255 ].…”

Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

“…The scheme of the experiments used in our current study were based on our previous published paper [48]. The dosages of morphine and buprenorphine were chosen based on our own studies [49], and the dosage of oxycodone was chosen based on our own unpublished data and literature [50,51]. The dosage of ketamine was chosen based on the literature [52].…”