title: Astrocyte contributes to pain development via MMP2-JNK1/2 signaling in a mouse model of complex regional pain syndrome.
abstract: BACKGROUND
  The activation of spinal glial cells (astrocyte and microglia) is reported in patient with complex regional pain syndrome (CRPS). However, the roles of spinal glial activities in the pathophysiology of CRPS are unclear. Here, we explored the roles of spinal astrocyte and microglia and the molecular mechanisms underlying CRPS using a mouse model of chronic post-ischemia pain (CPIP).
  
  
  RESULTS
  CPIP injury increased the level of glial fibrillary acidic protein (GFAP, reactive astrocyte biomarker), but had no significant impact on ionized calcium binding adaptor molecule 1 (IBA1, reactive microglia biomarker), in the ipsilateral dorsal horn on post-injury day (PID) 3 when the pain threshold started to reduce significantly. Astrocytic inhibition with fluorocitrate but not microglial inhibition with minocycline attenuated the development of allodynia in CPIP-injured mice, which was concomitant with increased spinal levels of phosphorylated c-jun N-terminal kinase 1/2 (pJNK1/2) on PID 3. Furthermore, the intrathecal administration of SP600125 (JNK inhibitor) prevented the development of allodynia in CPIP-injured mice. Double immunofluorescence staining showed that pJNK1/2 was mainly co-localized with GFAP. Subsequently, increased levels of pJNK1/2 were reversed by intrathecal fluorocitrate. Furthermore, the level of spinal matrix metalloproteinase-2 (MMP2) was increased and mainly expressed in NeuN (neuron biomarker) on PID 3 in the CPIP-injured mice, while intrathecal APR 100 (MMP2 inhibitor) delayed the development of allodynia and decreased spinal levels of GFAP and pJNK1/2 on PID 3.
  
  
  CONCLUSIONS
  This study shows that activation of astrocyte MMP2/JNK1/2 signaling pathway contributes to the pathogenesis of pain hypersensitivity in the CPIP model.
authors.affiliation: Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China; Department of Anesthesiology and Pain Medicine, Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Tian
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Chaoliang
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Anesthesiology and Pain Medicine, Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Sookja Kim
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China. Electronic address: cheucw@hku.hk.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Cheung
authors.affiliation: Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, China. Electronic address: qulianguo2011@163.com.
authors.forename: Qulian
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D020918:Complex Regional Pain Syndromes / Q000503:physiopathology*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia; D007150:Immunohistochemistry; D007511:Ischemia / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C528900:glial fibrillary astrocytic protein, mouse; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Astrocyte; Chronic post-ischemia pain; Matrix metalloproteinase-2; Spinal cord; c-jun N-terminal kinase