Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2.
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.
Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
De-Li
DL
Cao
Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China; Department of Anatomy, Medical School of Nantong University, Nantong, Jiangsu 226001, China.
Zhi-Jun
ZJ
Zhang
Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Rou-Gang
RG
Xie
Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
Bao-Chun
BC
Jiang
Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Ru-Rong
RR
Ji
Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China. Electronic address: gaoyongjing@hotmail.com.
Yong-Jing
YJ
Gao
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000378:metabolism* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000209:etiology / Q000473:pathology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors
D054360:Chemokine CXCL1; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; D016194:Receptors, N-Methyl-D-Aspartate; C112019:SB 225002; D005620:Freund's Adjuvant; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D010751:Phosphopyruvate Hydratase
Astrocytes; Astroglial–neuronal interaction; COX-2; CXCL1; CXCR2; Chemokines; Complete Freund's adjuvant; ERK; Inflammatory pain