CXCL10/CXCR3 Signaling in the DRG Exacerbates Neuropathic Pain in Mice
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ORIGINAL ARTICLE
CXCL10/CXCR3 Signaling in the DRG Exacerbates Neuropathic Pain in Mice Yan-Fang Kong1 • Wei-Lin Sha1 • Xiao-Bo Wu1 • Lin-Xia Zhao1 • Ling-Jie Ma1 • Yong-Jing Gao1,2
Received: 21 February 2020 / Accepted: 22 June 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Abstract Chemokines and receptors have been implicated in the pathogenesis of chronic pain. Here, we report that spinal nerve ligation (SNL) increased CXCR3 expression in dorsal root ganglion (DRG) neurons, and intra-DRG injection of Cxcr3 shRNA attenuated the SNL-induced mechanical allodynia and heat hyperalgesia. SNL also increased the mRNA levels of CXCL9, CXCL10, and CXCL11, whereas only CXCL10 increased the number of action potentials (APs) in DRG neurons. Furthermore, in Cxcr3-/- mice, CXCL10 did not increase the number of APs, and the SNL-induced increase of the numbers of APs in DRG neurons was reduced. Finally, CXCL10 induced the activation of p38 and ERK in ND7-23 neuronal cells and DRG neurons. Pretreatment of DRG neurons with the P38 inhibitor SB203580 decreased the number of APs induced by CXCL10. Our data indicate that CXCR3, activated by CXCL10, mediates p38 and ERK activation in DRG neurons and enhances neuronal excitability, which contributes to the maintenance of neuropathic pain. Keywords CXCR3 CXCL10 DRG Neuropathic pain Mice
Yan-Fang Kong and Wei-Lin Sha have contributed equally to this work. & Yong-Jing Gao [email protected]; [email protected] 1
Institute of Pain Medicine, Institute of Nautical Medicine, Nantong University, Nantong 226019, China
2
Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
Introduction Neuropathic pain is caused by disease or injury of the sensory nervous system and affects up to 8% of the population [1]. However, the mechanisms underlying neuropathic pain remains elusive. Accumulating evidence supports the idea that chemokine-mediated neuroinflammation plays an important role in the development and maintenance of neuropathic pain [2–4]. Several chemokines, such as CX3CL1, CCL2, CXCL1, CXCL13, and CXCL10 are increased in the spinal cord after tissue inflammation or nerve injury and contribute to inflammatory pain and neuropathic pain via different forms of neuron–glial interaction [5–9]. However, the roles and mechanisms of chemokines and chemokine receptors in the dorsal root ganglion (DRG) in mediating chronic pain have been less investigated. CXC chemokine receptor 3 (CXCR3), the receptor of the three ligands CXCL9, CXCL10, and CXCL11, is expressed in various cells, including endothelial cells, monocytes, T cells, and dendritic cells [10]. The activation of CXCR3 by its ligands contributes to the progression of autoimmune diseases and infections [10, 11]. Recent studies have shown that CXCR3 is expressed in spinal neurons and is increased after spinal nerve ligation (SNL) [7] or inoculation of cancer cells into the tibia [12]. SNL also increases the expression of CXCL9, CXCL10, and
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