Skip to main content
SpringerLink
Log in

JNK in spinal cord facilitates bone cancer pain in rats through modulation of CXCL1

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

In patients with advanced cancer, cancer-induced bone pain (CIBP) is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase (JNK) and chemokine (C-X-C motif) ligand 1 (CXCL1) have been shown to participate in several chronic pain processes, we investigated the role of JNK and CXCL1 in CIBP and the relationship between them. A rat bone cancer pain model was established by intramedullary injection of Walker 256 rat gland mammary carcinoma cells into the left tibia of Sprague-Dawley rats. As a result, intramedullary injection of Walker 256 carcinoma cells induced significant bone destruction and persistent pain. Both phosphorylated JNK1 (pJNK1) and pJNK2 showed time-dependent increases in the ipsilateral spinal cord from day 7 to day 18 after tumor injection. Inhibition of JNK activation by intrathecal administration of SP600125, a selective pJNK inhibitor, attenuated mechanical allodynia and heat hyperalgesia caused by tumor inoculation. Tumor cell inoculation also induced robust CXCL1 upregulation in the ipsilateral spinal cord on day 18 after tumor injection. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody showed a stable analgesic effect. Intrathecal administration of SP600125 reduced CXCL1 increase in the spinal cord, whereas inhibition of CXCL1 in the spinal cord showed no influence on JNK activation. Taken together, these results suggested that JNK activation in spinal cord contributed to the maintenance of CIBP, which may act through modulation of CXCL1. Inhibition of the pJNK/CXCL1 pathway may provide a new choice for treatment of CIBP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Montiel-Ruiz RM, Acosta-Gonzalez RI, Jimenez Andrade JM. Bone cancer pain: from preclinical pharmacology to clinical trials. Gac Med Mex, 2013,149(2):204–211

    PubMed  Google Scholar 

  2. Zhang RX, Liu B, Li A, et al. Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. Neuroscience, 2008, 154(4):1533–1538

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Currie GL, Delaney A, Bennett MI, et al. Animal models of bone cancer pain: systematic review and meta-analyses. Pain, 2013,154(6):917–926

    Article  PubMed  Google Scholar 

  4. Shen W, Hu XM, Liu YN, et al. CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord. J Neuroinflammation, 2014,11(1):1–14

    Article  Google Scholar 

  5. Mantyh P. Bone cancer pain: causes, consequences, and therapeutic opportunities. Pain, 2013,154(Suppl 1):S54–S62

    Article  PubMed  Google Scholar 

  6. Gao YJ, Ji RR. Activation of JNK pathway in persistent pain. Neurosci Lett, 2008,437(3):180–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Gao YJ, Zhang L, Samad OA, et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci, 2009, 29(13):4096–4108

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Gao YJ, Xu ZZ, Liu YC, et al. The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain, 2010,148(2):309–319

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Zhuang ZY, Wen YR, Zhang DR, et al. 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(13):3551–3360

    Article  CAS  PubMed  Google Scholar 

  10. Wang JG, Strong JA, Xie W, et al. The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol Pain, 2008,4(39):1–15

    Google Scholar 

  11. Dong F, Du YR, Xie W, et al. Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the proinflammatory cytokine GRO/KC. Neurosci Bull, 2012,28(2):155–164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Yang RH, Strong JA, Zhang JM. NF-kappaB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons. Mol Pain, 2009,5:26

    Article  PubMed Central  PubMed  Google Scholar 

  13. Qin X, Wan Y, Wang X. CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J Neurosci Res, 2005,82(1): 51–62

    Article  CAS  PubMed  Google Scholar 

  14. Zhang ZJ, Cao DL, Zhang X, et al. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain, 2013,154(10):2185–2197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Medhurst SJ, Walker K, Bowes M, et al. A rat model of bone cancer pain. Pain, 2002,96(1–2):129–140

    Article  CAS  PubMed  Google Scholar 

  16. Mao-Ying QL, Zhao J, Dong ZQ, et al. 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(4):1292–1298

    Article  CAS  PubMed  Google Scholar 

  17. Wang XW, Hu S, Mao-Ying QL, et al. Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats. Mol Brain, 2012,5:21

    Article  PubMed Central  PubMed  Google Scholar 

  18. Gao YJ, Cheng JK, Zeng Q, et al. Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol, 2009,219(1):146–155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Hargreaves K, Dubner R, Brown F, et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, 1988,32(1):77–88

    Article  CAS  PubMed  Google Scholar 

  20. Zhou LJ, Ren WJ, Zhong Y, et al. Limited BDNF contributes to the failure of injury to skin afferents to produce a neuropathic pain condition. Pain, 2010,148(1): 148–157

    Article  CAS  PubMed  Google Scholar 

  21. Hartung JE, Ciszek BP, Nackley AG. beta2-and beta3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines. Pain, 2014,155(7):1346–1355

    Article  CAS  PubMed  Google Scholar 

  22. Bogoyevitch MA, Kobe B. Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev, 2006,70(4):1061–1095

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. White FA, Jung H, Miller RJ. Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci USA, 2007,104(51):20 151–20 158

    Article  CAS  Google Scholar 

  24. Zhang J, Shi XQ, Echeverry S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci, 2007, 27(45):12 396–12 406

    Article  CAS  Google Scholar 

  25. Liu YL, Zhou LJ, Hu NW, et al. Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology, 2007,52(3):708–715

    Article  CAS  PubMed  Google Scholar 

  26. McTigue DM, Tani M, Krivacic K, et al. Selective chemokine mRNA accumulation in the rat spinal cord after contusion injury. J Neurosci Res, 1998,53(3):368–376

    Article  CAS  PubMed  Google Scholar 

  27. Valles A, Grijpink-Ongering L, de Bree FM, et al. Differential regulation of the CXCR2 chemokine network in rat brain trauma: implications for neuroimmune interactions and neuronal survival. Neurobiol Dis, 2006,22(2):312–322

    Article  CAS  PubMed  Google Scholar 

  28. Horuk R, Martin AW, Wang Z, et al. Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol, 1997,158(6):2882–2890

    CAS  PubMed  Google Scholar 

  29. Nguyen D, Stangel M. Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells. Brain Res Dev Brain Res, 2001,28(1):77–81

    Article  Google Scholar 

  30. Omari KM, John GR, Sealfon SC, et al. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain, 2005,128(5):1003–1015

    Article  PubMed  Google Scholar 

  31. Filipovic R, Jakovcevski I, Zecevic N. GRO-alpha and CXCR2 in the human fetal brain and multiple sclerosis lesions. Dev Neurosci, 2003,25(2–4):279–290

    Article  CAS  PubMed  Google Scholar 

  32. Popivanova BK, Koike K, Tonchev AB, et al. Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptor CXCR2 in monkey hippocampus after ischemiareperfusion. Brain Res, 2003,970(1–2):195–204

    Article  CAS  PubMed  Google Scholar 

  33. Xu J, Zhu MD, Zhang X, et al. NFkappaB-mediated CXCL1 production in spinal cord astrocytes contributes to the maintenance of bone cancer pain in mice. J Neuroinflammation, 2014,11:38

    Article  PubMed Central  PubMed  Google Scholar 

  34. Lo HM, Lai TH, Li CH, et al. TNF-alpha induces CXCL1 chemokine expression and release in human vascular endothelial cells in vitro via two distinct signaling pathways. Acta Pharmacol Sin, 2014,35(3): 339–350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Zhong-liang Wang  (汪忠良) & Rui-guang Zhang  (张瑞光)

  2. Department of Endocrinology, Wuhan Medical and Health Center for Women and Children, Wuhan, 430015, China

    Ting-ting Du  (杜婷婷)

Authors
  1. Zhong-liang Wang  (汪忠良)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting-ting Du  (杜婷婷)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui-guang Zhang  (张瑞光)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui-guang Zhang  (张瑞光).

Additional information

This project was supported by the National Natural Science Foundation of China (No. 81172150).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Zl., Du, Tt. & Zhang, Rg. JNK in spinal cord facilitates bone cancer pain in rats through modulation of CXCL1. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 88–94 (2016). https://doi.org/10.1007/s11596-016-1547-1

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-016-1547-1

Key words

Search

Navigation