期刊论文详细信息
Journal of Neuroinflammation
CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord
Chao Song2  Chen-Chen Wang2  Li-Ping Chen1  Yuan Han2  Yan-Nan Liu2  Xue-Ming Hu1  Wen Shen1 
[1] Department of Pain Medicine, The Affiliated Hospital of Xuzhou Medical College, 99 Huaihai West Road, Xuzhou 221002, People’s Republic of China;Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, 209 Tongshan Road, Xuzhou 221002, People’s Republic of China
关键词: Bone cancer pain;    Spinal cord;    Microglia;    Astrocytes;    Neurons;    Chemokine;    CXCR4;    CXCL12;   
Others  :  804763
DOI  :  10.1186/1742-2094-11-75
 received in 2013-11-26, accepted in 2014-04-03,  发布年份 2014
PDF
【 摘 要 】

Background

Previous studies have demonstrated that chemokine CXCL12 and its receptor CXCR4 are critical for pain sensitization, but the mechanisms involved are not clear. In this study, we investigated the specific cellular mechanisms of CXCL12/CXCR4 chemokine signaling in the development and maintenance of bone cancer pain after tumor cell implantation (TCI).

Methods

TCI in the tibial cavity of rats was used to establish a bone cancer pain model. Mechanical allodynia and thermal hyperalgesia were determined by measuring the paw withdrawal threshold and latency, respectively. The protein expression and cellular localization of CXCL12 and CXCR4 were detected by western blot and immunofluorescence staining. The sensitization of neurons, activation of astrocytes and microglia were examined by observing the immunofluorescence intensity of c-Fos, GFAP and IBA1.

Results

Our results demonstrated that CXCL12 was upregulated in a time-related manner, both in the dorsal root ganglia and spinal cord after TCI. Spinal CXCL12 was predominately expressed in astrocytes, and an intrathecal injection of astrocyte metabolic inhibitor fluorocitrate or selective JNK inhibitor SP600125 abolished TCI-induced CXCL12 production. A single intrathecal injection of a CXCL12 neutralizing antibody (10 μg/10 μl) at day 10 after TCI transiently reversed bone cancer pain in a dose-dependent manner. Whereas repetitive intrathecal administration of a CXCL12 neutralizing antibody (10 μg/10 μl, once a day from day 3 to 5 after TCI) significantly delayed the onset of TCI-induced pain behaviors for nearly five days. Spinal CXCR4 was also upregulated after TCI and colocalized with neurons, astrocytes and microglia. Blocking CXCR4 suppressed TCI-induced activation of neurons, astrocytes and microglia in the spinal cord at day 14. Repeated intrathecal administration of AMD3100 (5 μg/10 μl, once a day for three days) significantly delayed and suppressed the initiation and persistence of bone cancer pain in the early phase (at day 5, 6 and 7 after TCI) and in the late phase (at day 12, 13 and 14 after TCI) of bone cancer, respectively.

Conclusions

Taken together, these results demonstrate that CXCL12/CXCR4 signaling contributed to the development and maintenance of bone cancer pain via sensitizing neurons and activating astrocytes and microglia. Additionally, this chemokine signaling may be a potential target for treating bone cancer pain.

【 授权许可】

   
2014 Shen et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140708065113898.pdf 1859KB PDF download
Figure 9. 109KB Image download
Figure 8. 126KB Image download
Figure 7. 191KB Image download
Figure 6. 87KB Image download
Figure 5. 115KB Image download
Figure 4. 112KB Image download
Figure 3. 58KB Image download
Figure 2. 176KB Image download
Figure 1. 76KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】
  • [1]Jimenez-Andrade JM, Bloom AP, Stake JI, Mantyh WG, Taylor RN, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW: Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J Neurosci 2010, 30:14649-14656.
  • [2]Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006, 12:6243s-6249s.
  • [3]Goblirsch MJ, Zwolak P, Clohisy DR: Advances in understanding bone cancer pain. J Cell Biochem 2005, 96:682-688.
  • [4]Middlemiss T, Laird BJ, Fallon MT: Mechanisms of cancer-induced bone pain. Clin Oncol (R CollRadiol) 2011, 23:387-392.
  • [5]Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP: Molecular mechanisms of cancer pain. Nat Rev Cancer 2002, 2:201-209.
  • [6]Jimenez-Andrade JM, Mantyh WG, Bloom AP, Ferng AS, Geffre CP, Mantyh PW: Bone cancer pain. Ann N Y Acad Sci 2010, 1198:173-181.
  • [7]Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR, Mantyh PW: Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 1999, 19:10886-10897.
  • [8]Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM: Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain 2009, 13:138-145.
  • [9]Milligan ED, Watkins LR: Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009, 10:23-36.
  • [10]Cao H, Zhang YQ: Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 2008, 32:972-983.
  • [11]Gao YJ, Ji RR: Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 2010, 126:56-68.
  • [12]Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10:1361-1368.
  • [13]Li M, Ransohoff RM: Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 2008, 84:116-131.
  • [14]do Carmo A, Patricio I, Cruz MT, Carvalheiro H, Oliveira CR, Lopes MC: CXCL12/CXCR4 promotes motility and proliferation of glioma cells. Cancer Biol Ther 2010, 9:56-65.
  • [15]Wang Y, Huang J, Li Y, Yang GY: Roles of chemokine CXCL12 and its receptors in ischemic stroke. Curr Drug Targets 2012, 13:166-172.
  • [16]Reaux-Le Goazigo A, Rivat C, Kitabgi P, Pohl M, MelikParsadaniantz S: Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance. Eur J Neurosci 2012, 36:2619-2631.
  • [17]Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ: Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 2001, 21:5027-5035.
  • [18]Bhangoo SK, Ren D, Miller RJ, Chan DM, Ripsch MS, Weiss C, McGinnis C, White FA: CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav Immun 2007, 21:581-591.
  • [19]Dubovy P, Klusakova I, Svizenska I, Brazda V: Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain. Histochem Cell Biol 2010, 133:323-337.
  • [20]Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA: CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun 2011, 25:565-573.
  • [21]Han Y, He T, Huang DR, Pardo CA, Ransohoff RM: TNF-alpha mediates SDF-1 alpha-induced NF-kappa B activation and cytotoxic effects in primary astrocytes. J Clin Invest 2001, 108:425-435.
  • [22]Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983, 16:109-110.
  • [23]Mao-Ying QL, Zhao J, Dong ZQ, Wang J, Yu J, Yan MF, Zhang YQ, Wu GC, Wang YQ: A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Biochem Biophys Res Commun 2006, 345:1292-1298.
  • [24]Medhurst SJ, Walker K, Bowes M, Kidd BL, Glatt M, Muller M, Hattenberger M, Vaxelaire J, O’Reilly T, Wotherspoon G, Winter J, Green J, Urban L: A rat model of bone cancer pain. Pain 2002, 96:129-140.
  • [25]Xu JJ, Walla BC, Diaz MF, Fuller GN, Gutstein HB: Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance. Anesth Analg 2006, 103:714-720.
  • [26]Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53:55-63.
  • [27]Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32:77-88.
  • [28]Liu WT, Han Y, Li HC, Adams B, Zheng JH, Wu YP, Henkemeyer M, Song XJ: An in vivo mouse model of long-term potentiation at synapses between primary afferent C-fibers and spinal dorsal horn neurons: essential role of EphB1 receptor. Mol Pain 2009, 5:29. BioMed Central Full Text
  • [29]Liu WT, Han Y, Liu YP, Song AA, Barnes B, Song XJ: Spinal matrix metalloproteinase-9 contributes to physical dependence on morphine in mice. J Neurosci 2010, 30:7613-7623.
  • [30]Hu JH, Zheng XY, Yang JP, Wang LN, Ji FH: Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer-induced bone pain in rats. Neurosci Lett 2012, 517:60-63.
  • [31]Khasabova IA, Stucky CL, Harding-Rose C, Eikmeier L, Beitz AJ, Coicou LG, Hanson AE, Simone DA, Seybold VS: Chemical interactions between fibrosarcoma cancer cells and sensory neurons contribute to cancer pain. J Neurosci 2007, 27:10289-10298.
  • [32]Hu J-H, Yang J-P, Liu L, Li C-F, Wang L-N, Ji F-H, Cheng H: Involvement of CX3CR1 in bone cancer pain through the activation of microglia p38 MAPK pathway in the spinal cord. Brain Res 2012, 1465:1-9.
  • [33]Vit JP, Ohara PT, Tien DA, Fike JR, Eikmeier L, Beitz A, Wilcox GL, Jasmin L: The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception. Pain 2006, 120:188-201.
  • [34]Gao YJ, Ji RR: Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010, 7:482-493.
  • [35]Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR: A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006, 26:3551-3560.
  • [36]Wang XW, Hu S, Mao-Ying QL, Li Q, Yang CJ, Zhang H, Mi WL, Wu GC, Wang YQ: Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats. Mol Brain 2012, 5:21. BioMed Central Full Text
  • [37]Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009, 29:4096-4108.
  • [38]Zhang ZJ, Cao DL, Zhang X, Ji RR, Gao YJ: Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 2013, 154:2185-2197.
  • [39]Bertolini F, Dell’Agnola C, Mancuso P, Rabascio C, Burlini A, Monestiroli S, Gobbi A, Pruneri G, Martinelli G: CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma. Cancer Res 2002, 62:3106-3112.
  • [40]Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ: WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 2013, 123:2268-2286.
  • [41]White FA, Jung H, Miller RJ: Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 2007, 104:20151-20158.
  • [42]Hang LH, Shao DH, Chen Z, Chen YF, Shu WW, Zhao ZG: Involvement of spinal CC chemokine ligand 5 in the development of bone cancer pain in rats. Basic Clin Pharmacol Toxicol 2013, 113:325-328.
  • [43]Knerlich-Lukoschus F, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J: Spatiotemporal CCR1, CCL3(MIP-1alpha), CXCR4, CXCL12(SDF-1alpha) expression patterns in a rat spinal cord injury model of posttraumatic neuropathic pain. J Neurosurg Spine 2011, 14:583-597.
  • [44]Ohtani Y, Minami M, Kawaguchi N, Nishiyori A, Yamamoto J, Takami S, Satoh M: Expression of stromal cell-derived factor-1 and CXCR4 chemokine receptor mRNAs in cultured rat glial and neuronal cells. Neuroscience letters 1998, 249:163-166.
  • [45]Zhang ZJ, Dong YL, Lu Y, Cao S, Zhao ZQ, Gao YJ: Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J Neuroinflammation 2012, 9:136. BioMed Central Full Text
  • [46]Wei F, Guo W, Zou S, Ren K, Dubner R: Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci 2008, 28:10482-10495.
  • [47]Ji R-R, Berta T, Nedergaard M: Glia and pain: Is chronic pain a gliopathy? Pain 2013, 154:S10-S28.
  • [48]Liu S, Liu YP, Song WB, Song XJ: EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord. Pain 2013, 154:2823-2835.
  • [49]Jarvis MF: The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci 2010, 33:48-57.
  • [50]Cartier L, Hartley O, Dubois-Dauphin M, Krause KH: Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev 2005, 48:16-42.
  • [51]Teicher BA, Fricker SP: CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010, 16:2927-2931.
  • [52]Ji RR, Gereau RW, Malcangio M, Strichartz GR: MAP kinase and pain. Brain Res Rev 2009, 60:135-148.
  • [53]Shi TJ, Liu SX, Hammarberg H, Watanabe M, Xu ZQ, Hokfelt T: Phospholipase C{beta}3 in mouse and human dorsal root ganglia and spinal cord is a possible target for treatment of neuropathic pain. Proc Natl Acad Sci U S A 2008, 105:20004-20008.
  • [54]Xu JT, Tu HY, Xin WJ, Liu XG, Zhang GH, Zhai CH: Activation of phosphatidylinositol 3-kinase and protein kinase B/Akt in dorsal root ganglia and spinal cord contributes to the neuropathic pain induced by spinal nerve ligation in rats. Exp Neurol 2007, 206:269-279.
  • [55]Keating GM: Plerixafor: a review of its use in stem-cell mobilization in patients with lymphoma or multiple myeloma. Drugs 2011, 71:1623-1647.
  • [56]Burger JA, Stewart DJ: CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert OpinInvestig Drugs 2009, 18:481-490.
  • [57]Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD: CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 2004, 64:8604-8612.
  • [58]Lee HJ, Kim SW, Kim HY, Li S, Yun HJ, Song KS, Kim S, Jo DY: Chemokine receptor CXCR4 expression, function, and clinical implications in gastric cancer. Int J Oncol 2009, 34:473-480.
  • [59]Ooi LL, Dunstan CR: CXCL12/CXCR4 axis in tissue targeting and bone destruction in cancer and multiple myeloma. J Bone Miner Res 2009, 24:1147-1149.
  文献评价指标  
  下载次数:381次 浏览次数:142次