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

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.

Intervertebral foramen injection of plerixafor attenuates CCD-induced low back pain in rats through down-regulation of Nav1.8 and Nav1.9

“…Using CCD model, we found that the expression level of CXCR4 in compressed DRG dramatically increased revealed by immuno uorescent staining which was in accordance with a recent study [12]. The functional nature of the up-regulated CXCR4 was identi ed by our siRNA knockdown assay in which intraganglionar microinjection with CXCR4 siRNA obviously attenuated CCD-induced multiple pain behaviors.…”

“…Our previous study has showed that activation of CXCR4 could directly modulate primary neuronal excitability by mediating the up-regulation of Nav1.8 under in ammatory pain state [24]. Interestingly, the CXCR4 expression also signi cantly increased in the compressed DRG from CCD mice [12]. Whether the Nav1.8 and Nav1.9 was the downstream effector target for CCD-induced CXCR4 activation remains unclear.…”

“…Much evidence has accumulated that CXCR4 chemokine signaling contributes to the development and maintenance of chronic pain [9][10][11]. A recent study have demonstrated that intraperitoneal injection of plerixafor (AMD3100), a selective antagonist for CXCR4, which has been approved for mobilization of hematopoietic stem cells clinically by the U.S. Food and Drug Administration in 2008, signi cantly ameliorated CCD-induced mechanical and thermal hyperalgesia, suggesting CXCR4 might be an adequate analgesic target [12][13][14]. As we known, the CXCR4 is widely located in the nervous system and distributed in various kinds of cells [9,15].…”

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

“…Several GPCRs involved in pro-inflammatory pathways, including CCR1 , CCRL2 , CNR1 , CXCR4 , F2R , CHRM1 [66; 68] were found to increase in abundance in cultured DRGs. GPCRs found to be decreased in culture included DRD5 , HTR5A , HTR6 , and some metabotropic glutamate receptors ( GRM s) like GRM4, GRM5 (which was not detected) and GRM7 , all of which have been shown to be highly neural tissue enriched in humans (based on neural proportion score > 0.9 in Ray et al [47]).…”

A New Method for Primary Culture of Mouse Dorsal Root Ganglion Neurons

“…Spinal DRGn are afferent neurons of peripheral nervous system and primary neurons of sensory conduction system. With the increasing research on the nervous system, such as the pain mechanism of diseases [1][2][3], spinal cord injury repair [4,5], electrophysiological research [6][7][8][9], it is necessary to establish a simple and easy-to-obtain primary nerve cell culture scheme.…”