Central administration of C-X-C chemokine receptor type 4 antagonist alleviates the development and maintenance of peripheral neuropathic pain in mice.

Xin Luo,Liting Sun,Zhengyuan Xia,Qiu Qiu,Chi Wai Cheung,Sookja Kim Chung,Wai Lydia Tai,Sam Eldabe

doi:10.1371/journal.pone.0104860

Xin Luo, Liting Sun + Show 6 more

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https://doi.org/10.1371/journal.pone.0104860

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Journal: PloS one	Publication Date: Aug 13, 2014
Citations: 54	License type: CC BY 4.0

Affiliation: University of Hong Kong

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.

Highlights

Chemokine receptors have been intensively studied for their roles in nociception and considered novel targets for neuropathic pain therapy [1]
CXCL12 and CXCR4 were positive in neurons, astrocytes, microglia/macrophages, and leukocytes in the lumbar spinal cord and their spinal immunoreactivity was found to be increased in a central neuropathic pain model [10]
Any impairment in motor function might affect the assessment of pain and intrathecal AMD3100 would not be suitable for potential analgesic treatment if that was the case

Summary

Introduction

Chemokine receptors have been intensively studied for their roles in nociception and considered novel targets for neuropathic pain therapy [1]. CXCR4 is widely expressed in the peripheral and central nervous system (PNS and CNS) and exerts numerous important functions, such as modulation of neurotransmission, synaptic plasticity, and neuroglial interactions [2]. Increasing number of studies reported roles of CXCR4 in pain processing in the PNS, as CXCR4 is expressed on primary sensory neurons, satellite cells, Schwann cells, and endothelial cells in the peripheral nociceptive structure [3,4,5,6,7,8,9]. CXCL12 and CXCR4 were positive in neurons, astrocytes, microglia/macrophages, and leukocytes in the lumbar spinal cord and their spinal immunoreactivity was found to be increased in a central neuropathic pain model [10]. The activation of spinal CXCR4 by the intrathecal administration of CXCL12 has been found to induce mechanical allodynia for 3 days, which could be reversed by a CXCR4-neutralizing antibody given intrathecally [9]

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