Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2

• Published in: Experimental neurology 2014-11, Vol.261, p.328-336
• Main Authors: Cao, De-Li, Zhang, Zhi-Jun, Xie, Rou-Gang, Jiang, Bao-Chun, Ji, Ru-Rong, Gao, Yong-Jing
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - drug effects; Astroglial–neuronal interaction; Chemokine CXCL1 - metabolism; Chemokine CXCL1 - pharmacology; Chemokines; Complete Freund's adjuvant; COX-2; CXCL1; CXCR2; Cyclooxygenase 2 - metabolism; Disease Models, Animal; ERK; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - genetics; Freund's Adjuvant - toxicity; Inflammation - chemically induced; Inflammation - complications; Inflammatory pain; Male; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Inbred ICR; Neurons - drug effects; Neurons - metabolism; Pain - etiology; Pain - pathology; Phenylurea Compounds - pharmacology; Phosphopyruvate Hydratase - metabolism; Receptors, Interleukin-8B - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Spinal Cord - pathology; Time Factors
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.05.014

Recent studies have shown that CXCL1 upregulation in spinal astrocytes is involved in the maintenance of neuropathic pain. However, whether and how CXCL1 regulates inflammatory pain remains unknown. Here we show that intraplantar injection of CFA increased mRNA and protein expressions of CXCL1 and its major receptor CXCR2 in the spinal cord at 6h and 3days after the injection. Immunofluorescence double staining showed that CXCL1 and CXCR2 were expressed in spinal astrocytes and neurons, respectively. Intrathecal injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 attenuated CFA-induced mechanical and heat hypersensitivity on post-CFA day 3. Patch-clamp recordings showed that CXCL1 potentiated NMDA-induced currents in lamina II neurons via CXCR2, and this potentiation was further increased in CFA-treated mice. Furthermore, intrathecal injection of CXCL1 increased COX-2 expression in dorsal horn neurons, which was blocked by pretreatment with SB225002 or MEK (ERK kinase) inhibitor PD98059. Finally, pretreatment with SB225002 or PD98059 decreased CFA-induced heat hyperalgesia and COX-2 mRNA/protein expression and ERK activation in the spinal cord. Taken together, our data suggest that CXCL1, upregulated and released by spinal astrocytes after inflammation, acts on CXCR2-expressing spinal neurons to increase ERK activation, synaptic transmission and COX-2 expression in dorsal horn neurons and contributes to the pathogenesis of inflammatory pain. •CFA induces upregulations of CXCL1 and CXCR2 in the spinal cord.•CXCL1 and CXCR2 are respectively expressed in spinal astrocytes and neurons.•Inhibition of CXCL1 or CXCR2 alleviates CFA-induced inflammatory pain.•CXCL1 increases NMDA-induced currents of lamina II neurons & induces CXCR2/ERK dependent COX-2 expression in spinal neurons.