title: Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain.
abstract: BACKGROUND
  Neuropathic pain (NP) continues to be challenging to treat due to lack of effective drugs. Accumulating evidence elucidated that glia-mediated inflammatory reactions play a pivotal role in the introduction and development of NP. Besides, activation of the c-Jun N-terminal kinase (JNK)/monocyte chemoattractant protein-1 (MCP-1) pathway in astrocytes has been reported to be critical for spinal astrocytic activation and neuropathic pain development after spinal nerve ligation (SNL). Tanshinone IIA, a major active component of a traditional Chinese drug, Danshen, possesses potent immuno-suppressive activities. The present study was undertaken to assess whether intraperitoneal administration of tanshinone IIA sulfonate (TIIAS) has analgesic effect on SNL-induced neuropathic pain and whether the inhibition of astrocytic activation and JNK/MCP-1 pathway is involved in the analgesic effect of TIIAS.
  
  
  METHODS
  The effects of TIIAS on SNL-induced mechanical allodynia were assessed by behavioral testing. Immunofluorescence histochemical staining was used to detect changes of spinal astrocytes and spinal pJNK expression and localization. Immunofluorescence histochemistry and Western blot analysis were used to quantify the SNL-induced spinal pJNK expression after TIIAS administration. Enzyme-linked immunosorbent assay (ELISA) was used to detect the SNL-induced spinal expression of pro-inflammatory cytokines and MCP-1.
  
  
  RESULTS
  Our results indicated that intraperitoneal TIIAS up-regulated the mechanical paw withdrawal threshold (PWT) of NP, while astrocytic activation was suppressed and accompanied by the down-regulation of IL-1β and TNF-α expression, as well as JNK phosphorylation in the spinal dorsal horn. Additionally, the release of MCP-1 was dose dependently decreased. After co-treatment with TIIAS and JNK inhibitor (SP600125), no significant increases in mechanical PWT and MCP-1 expression were observed compared with the TIIAS-treated group.
  
  
  CONCLUSIONS
  The present results suggest that the analgesic effects of TIIAS in neuropathic pain are mainly mediated by the down-regulation of SNL-induced astrocytic activation, which is via the inhibition of JNK/MCP-1 pathway.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, People's Republic of China. fmmutangjun@qq.com.|Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, No. 145 West Changle Road, Xi'an, 710032, People's Republic of China. fmmutangjun@qq.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, People's Republic of China. zhuchaode@gmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, No. 1 Xinsi Road, Xi'an, 710038, People's Republic of China. tdlizhihong@163.com.
authors.forename: Zhi-hong
authors.initials: ZH
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, People's Republic of China. nzliuxiaoyu@163.com.
authors.forename: Xiao-yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, No. 169 West Changle Road, Xi'an, 710032, People's Republic of China. kqsunshukai@163.com.
authors.forename: Shu-kai
authors.initials: SK
authors.lastname: Sun
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, No. 169 West Changle Road, Xi'an, 710032, People's Republic of China. jpzhangting@163.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, People's Republic of China. zjluo@fmmu.edu.cn.
authors.forename: Zhuo-jing
authors.initials: ZJ
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, No. 145 West Changle Road, Xi'an, 710032, People's Republic of China. kouqiangzhanghui@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, People's Republic of China. nzliweiyan@163.com.
authors.forename: Wei-yan
authors.initials: WY
authors.lastname: Li
mesh_terms: D045784:Abietanes / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009069:Movement Disorders / Q000209:etiology; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D045784:Abietanes; D000700:Analgesics; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C021751:tanshinone