Central Administration of C-X-C Chemokine Receptor Type 4 Antagonist Alleviates the Development and Maintenance of Peripheral Neuropathic Pain in Mice

Abstract

AimTo explore the roles of C-X-C chemokine receptor type 4 (CXCR4) in spinal processing of neuropathic pain at the central nervous system (CNS).MethodsPeripheral neuropathic pain (PNP) induced by partial sciatic nerve ligation (pSNL) model was assessed in mice. Effects of a single intrathecal (central) administration of AMD3100 (intrathecal AMD3100), a CXCR4 antagonist, on pain behavior and pain-related spinal pathways and molecules in the L3-L5 spinal cord segment was studied compare to saline treatment.ResultsRotarod test showed that intrathecal AMD3100 did not impair mice motor function. In pSNL-induced mice, intrathecal AMD3100 delayed the development of mechanical allodynia and reversed the established mechanical allodynia in a dose-dependent way. Moreover, intrathecal AMD3100 downregulated the activation of JNK1 and p38 pathways and the protein expression of p65 as assessed by western blotting. Real-time PCR test also demonstrated that substance P mRNA was decreased, while adrenomedullin and intercellular adhesion molecule mRNA was increased following AMD3100 treatment.ConclusionOur results suggest that central (spinal) CXCR4 is involved in the development and maintenance of PNP and the regulation of multiple spinal molecular events under pain condition, implicating that CXCR4 would potentially be a therapeutic target for chronic neuropathic pain.

CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

“…In a partial sciatic nerve ligation (pSNL) model, we first reported the central roles of CXCL12/CXCR4 axis in neuropathic pain processing (Luo et al, 2014). Our study showed that a single intrathecal injection of AMD3100 attenuated established hyperalgesia by pSNL in a dosedependent manner.…”

“…Not only does CXCL12/CXCR4 axis modulate the neuromodulation, neuroprotection, and neuronal-glial interaction in normal conditions, it is also involved in the neurological disorder caused by human immunodeficiency virus (HIV) infection, tumor, stroke, and multiple sclerosis (Li and Ransohoff, 2008). In the last few years, an increasing number of pain research in CXCL12/CXCR4 axis have shown that it is an emerging neuromodulator in pathological pain (Bhangoo et al, 2009;Dubovy et al, 2010;Luo et al, 2014;Shen et al, 2014). Thus, in this article, the evidence for the involvement of CXCL12/CXCR4 axis in pathological pain is reviewed.…”

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

“…A growing number of studies have reported the effects of CXCL12/CXCR4 signaling on the pathogenesis of chronic pain [10,12,34]. However, few experiments have systemically assessed their roles in direct peripheral nerve injury-induced neuropathic pain.…”

“…dose of AMD3100 delays the development of neuropathic pain and ameliorates established neuropathic pain in mice, and the effect persists for [3 days [41]. Reaux-Le et al reported that a single i.t.…”

“…Stromal cell-derived factor-1a (SDF-1a), now also named CXCL12, belongs to the CXC subfamily and is a ligand for the G-protein-coupled receptor CXCR4. The binding of CXCL12 to CXCR4 activates multiple signaling pathways, including the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase-Akt, cAMP/ cAMP-dependent protein kinase, and phospholipase C pathways, and results in increased intracellular calcium levels and the release of cytokines by glial cells [8][9][10]. Increasing evidence suggests that CXCL12/CXCR4 play important roles in nociceptive signal processing [11][12][13][14].…”