title: 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 long-lasting 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, SNI-induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-α 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-α 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.
authors.affiliation: Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, 450001, China.|Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, 450001, China.|Department of Pharmacy, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Cunlong
authors.initials: C
authors.lastname: Kong
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, 450001, China.
authors.forename: Jun-Liang
authors.initials: JL
authors.lastname: Qian
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Quancheng
authors.initials: Q
authors.lastname: Kan
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. zhangw571012@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, 450001, China. jtxu@zzu.edu.cn.|Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. jtxu@zzu.edu.cn.
authors.forename: Ji-Tian
authors.initials: JT
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000503:physiopathology*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12
keywords: CXCL12; Extracellular signal-regulated kinase; Neuropathic pain; Spared nerve injury; Spinal cord; TNF-α