title: Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons.
abstract: Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms, including mechanical allodynia and heat hyperalgesia, but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, tumor necrosis factor-α induced robust CXCL1 expression via the activation of the c-jun N-terminal kinase. Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated extracellular signal-regulated kinase and cAMP response element binding protein, and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.
authors.affiliation: Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, China Department of Anatomy, Medical School of Nantong University, Nantong 226001, China Sensory Plasticity Laboratory, Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: De-Li
authors.initials: DL
authors.lastname: Cao
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis* / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D023063:Receptors, Interleukin-8B
keywords: Astrocytes; CXCL1; CXCR2; Chemokines; Neuron–glia interaction; Neuropathic pain