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

Joanna Bogacka,Jan Dobrogowski,Katarzyna Pawlik,Klaudia Kwiatkowski,Anna Przeklasa-Muszynska,Joanna Mika,Katarzyna Ciapała

doi:10.3389/fimmu.2020.01241

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.

Highlights

Neuropathic pain is associated with the dysfunction of or damage to the central or peripheral nervous system
The results of our research demonstrated that a single i.t. or i.p. administration of C021, a chemokine receptor 4 (CCR4) antagonist, dose dependently diminished neuropathic pain-related behaviors in constriction injury (CCI)-exposed mice
The spinal levels of CCL17 and CCL22 remained unchanged, unlike the level of CCL2, which was upregulated until day 14 after CCI

Summary

Introduction

Neuropathic pain is associated with the dysfunction of or damage to the central or peripheral nervous system. Despite many years of research in this field, the mechanism underlying the generation and persistence of this type of pain is still not fully understood, and this has resulted in a lack of appropriate and effective therapies. This is strictly due to the need for extended. Considering that neuronal [17] and non-neuronal cells [18, 19], including human microglia/macrophage [20], have been reported to express CCR4, we hypothesize that the blockade of this receptor may serve as a new target for neuropathic pain pharmacotherapy. The pronociceptive properties of CCL2 have already been described [23,24,25]

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