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

Abstract

Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced longlasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNIinduced a sustained increase in TNF-a expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-a synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-a might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…Increasing evidence supports a role of chemokines in pain control [14]. Xie and co-authors report an active role of the chemokine CCL2 in promoting central sensitization, longterm potentiation, and inflammatory pain [31].…”

“…In the last 5 years, the field has seen tremendous progress in the molecular and functional characterization of primary sensory neurons [6,7], neurocircuits of pain and itch [8][9][10], immune and glial modulation of pain and itch [11][12][13][14][15], molecular mechanisms of pain [16,17], and identification of brain signatures of pain [18]. Thus, it is timely to highlight the recent progress in a second special issue.…”

The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons

“…However, available data about the CXCR4 receptor behavior are contradictory. Whereas some authors, using different models, have demonstrated that CXCR4 activation may promote reversion of cellular damage induced by several insults [6,11,34], other authors have reported the opposite [15,16,17]. In fact, the activation of CXCR4 chemokine receptor led to detrimental effects in these recent studies [14,15,16,17].…”

“…Conversely, other authors have demonstrated beneficial effects on neuronal function by blocking CXCR4 with AMD3100 [13,16,17]. …”

“…It was also reported that CXCR4 chemokine receptor signaling mediated pain in diabetic neuropathy [15]. Upregulation of CXCR4 in the dorsal root ganglia and spinal cord contributes to the development and maintenance of neuropathic pain following nerve injury in rats [16]. Systemic inflammation induces anxiety disorder through the CXCR4/SDF-1α pathway [17].…”