Effect of CXCL12/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion

Yang Yu,Ni Fan,Xini Huang,Lintao Qu,Yuwei Di

doi:10.1038/s41598-017-05954-1

Abstract

Neuropathic pain is a complex, chronic pain state that often accompanies tissue damage, inflammation or injury of the nervous system. However the underlying molecular mechanisms still remain unclear. Here, we showed that CXCL12 and CXCR4 were upregulated in the dorsal root ganglion (DRG) after chronic compression of DRG (CCD), and some CXCR4 immunopositive neurons were also immunopositive for the nociceptive neuronal markers IB4, TRPV1, CGRP, and substance P. The incidence and amplitude of CXCL12-induced Ca2+ response in primary sensory neurons from CCD mice was significantly increased compared to those from control animals. CXCL12 depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2X rheobase in neurons from CCD mice. The mechanical and thermal hypernociception after CCD was attenuated by administration of a CXCR4 antagonist AMD3100. These findings suggest that CXCL12/CXCR4 signaling contributes to hypernociception after CCD, and targeting CXCL12/CXCR4 signaling pathway may alleviate neuropathic pain.

Highlights

Neuropathic pain is one common symptom under various pathological conditions, especially sciatica and low back pain
Several evidences have indicated that CXC motif ligand 12 (CXCL12)/CXC motif receptor 4 (CXCR4) signaling is enhanced within dorsal root ganglion (DRG) after chronic compression of DRG (CCD)
CXCR4 is typically expressed in subsets of immune cells to regulate immunity[17], CXCL12 and its cognate receptor CXCR4 are constitutively expressed in the DRG and spinal cord in small amount[18, 19]

Summary

Introduction

Neuropathic pain is one common symptom under various pathological conditions, especially sciatica and low back pain. Chronic compression of the dorsal root ganglion (CCD) is a typical model of neuropathic pain, which better mimics low back pain and sciatica in humans[3, 4]. In the rat model of spared nerve injury (SNI), the upregulation of chemokine CXCL12 in the DRG contributed to the development and maintenance of neuropathic pain via the activation of ERK pathway. We hypothesized that the upregulated CXCL12/CXCR4 signaling directly contribute to the hyperexcitability of DRG neurons after CCD and blocking CXCL12/CXCR4 signaling in DRG may help attenuate mechanical and thermal hypersensitity associated with CCD We tested this possibility with the use of behavioral testing, PCR, immunofluorescent labeling, calcium imaging, and whole-cell patch clamp recording

Methods

Results

Conclusion