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

Anna Piotrowska,Ewelina Rojewska,Katarzyna Ciapała,Joanna Mika,Katarzyna Pawlik,Klaudia Kwiatkowski

doi:10.3390/ijms222011074

Abstract

Recent findings have highlighted the roles of CXC chemokine family in the mechanisms of neuropathic pain. Our studies provide evidence that single/repeated intrathecal administration of CXCR2 (NVP-CXCR2-20) and CXCR3 ((±)-NBI-74330) antagonists explicitly attenuated mechanical/thermal hypersensitivity in rats after chronic constriction injury of the sciatic nerve. After repeated administration, both antagonists showed strong analgesic activity toward thermal hypersensitivity; however, (±)-NBI-74330 was more effective at reducing mechanical hypersensitivity. Interestingly, repeated intrathecal administration of both antagonists decreased the mRNA and/or protein levels of pronociceptive interleukins (i.e., IL-1beta, IL-6, IL-18) in the spinal cord, but only (±)-NBI-74330 decreased their levels in the dorsal root ganglia after nerve injury. Furthermore, only the CXCR3 antagonist influenced the spinal mRNA levels of antinociceptive factors (i.e., IL-1RA, IL-10). Additionally, antagonists effectively reduced the mRNA levels of pronociceptive chemokines; NVP-CXCR2-20 decreased the levels of CCL2, CCL6, CCL7, and CXCL4, while (±)-NBI-74330 reduced the levels of CCL3, CCL6, CXCL4, and CXCL9. Importantly, the results obtained from the primary microglial and astroglial cell cultures clearly suggest that both antagonists can directly affect the release of these ligands, mainly in microglia. Interestingly, NVP-CXCR2-20 induced analgesic effects after intraperitoneal administration. Our research revealed important roles for CXCR2 and CXCR3 in nociceptive transmission, especially in neuropathic pain.

Highlights

Despite numerous basic and clinical studies, the pathological mechanisms underlying neuropathic pain are still insufficiently understood, and, its treatment remains extremely difficult
NVP CXCR2 20 effectively reduced the mRNA levels of CCL2, CCL6, CCL7, and CXCL4; in contrast, (±)-NBI 74330 diminished the levels of CCL3, CCL6, CXCL4, and CXCL9, which indicates slightly different mechanisms of action
Our results obtained from primary microglial cell cultures suggest a direct effect of both antagonists on the release of pronociceptive cytokines by these cells (IL-1β, IL-18, CCL6-7, CXCL4, and CXCL9-10)

Summary

Introduction

Despite numerous basic and clinical studies, the pathological mechanisms underlying neuropathic pain are still insufficiently understood, and, its treatment remains extremely difficult. Neuropathic pain is not completely relieved by conventionally used analgesics and often becomes an ailment with no prospect of significant improvement [1,2]. Studies focusing on recognizing new factors playing fundamental roles in the pathogenesis of neuropathic pain are important [3]. Cytokines, including chemokines, mediate and coordinate the neuroimmune interactions occurring after injury to the nervous system [4]. Recent evidence has highlighted an important role for chemokines in neuropathic pain development [4,5,6,7].

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Discussion

Conclusion