Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Brain
Published in: Molecular Brain 1/2012

Open Access 01-12-2012 | Research

Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats

Authors: Xiao-Wei Wang, Shan Hu, Qi-Liang Mao-Ying, Qian Li, Chang-Jiang Yang, Hui Zhang, Wen-Li Mi, Gen-Cheng Wu, Yan-Qing Wang

Published in: Molecular Brain | Issue 1/2012

Login to get access

Abstract

Background

The most frequent pain in patients with metastatic breast and prostate cancer is bone pain, which can be severe and difficult to treat. The mechanisms underlying this pain remain unclear. Here we investigated the role of c-jun N-terminal kinase (JNK) pathway in the spinal cord in cancer-induced bone pain (CIBP).

Results

In this study, we used an established rat CIBP model to investigate the possible role of JNK activation in the spinal cord. After intra-tibial inoculation with Walker 256 rat mammary gland carcinoma cells, the rats displayed mechanical allodynia on day 5, which lasted to day 16. The activation of JNK in neurons and astrocytes in the spinal cord was found on day 12 and day 16 after intra-tibial inoculation with carcinoma cells. A single intrathecal injection with JNK inhibitor SP600125 by lumbar puncture attenuated mechanical allodynia on day 12, and repeated intrathecal injection of SP600126 from day 10 to day 14 had a cumulative analgesic effect on CIBP.

Conclusions

Taken together, our results demonstrated for the first time that JNK activation in the spinal cord is required in the maintenance of CIBP. Inhibition of the spinal JNK pathway may provide a new therapy for CIBP management.
Appendix
Available only for authorised users
Literature
1.
Lin A, Dibling B: The true face of JNK activation in apoptosis. Aging Cell. 2002, 1 (2): 112-116. 10.1046/j.1474-9728.2002.00014.x.CrossRefPubMed
2.
Cavalli V, Kujala P, Klumperman J, Goldstein LS: Sunday Driver links axonal transport to damage signaling. J Cell Biol. 2005, 168: 775-787. 10.1083/jcb.200410136.PubMedCentralCrossRefPubMed
3.
Wang W, Mei XP, Wei YY, Zhang MM, Zhang T, Wang W, Xu LX, Wu SX, Li YQ: Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain. Brain Behav Immun. 2011, 25: 1355-1366. 10.1016/j.bbi.2011.04.002.CrossRefPubMed
4.
5.
Whitmarsh AJ, Davis RJ: Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl). 1996, 74: 589-607. 10.1007/s001090050063.CrossRef
6.
Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I, Ji RR: 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: 309-319. 10.1016/j.pain.2009.11.017.PubMedCentralCrossRefPubMed
7.
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. 10.1523/JNEUROSCI.5290-05.2006.CrossRefPubMed
8.
Hao J, Liu MG, Yu YQ, Cao FL, Li Z, Lu ZM, Chen J: Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia. Neuroscience. 2008, 152: 1067-1075. 10.1016/j.neuroscience.2007.12.038.CrossRefPubMed
9.
Gao YJ, Cheng JK, Zeng Q, Xu ZZ, Decosterd I, Xu X, Ji RR: 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. 10.1016/j.expneurol.2009.05.006.PubMedCentralCrossRefPubMed
10.
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 the spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009, 29: 4096-4108. 10.1523/JNEUROSCI.3623-08.2009.PubMedCentralCrossRefPubMed
11.
12.
Mercadante S: Malignant bone pain: pathophysiology and treatment. Pain. 1997, 69: 1-18. 10.1016/S0304-3959(96)03267-8.CrossRefPubMed
13.
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. 10.1016/S0304-3959(01)00437-7.CrossRefPubMed
14.
Menendez L, Lastra A, Fresno MF, Llames S, Meana A, Hidalgo A, Baamonde A: Initial thermal heat hypoalgesia and delayed hyperalgesia in a murine model of bone cancer pain. Brain Res. 2003, 969: 102-109. 10.1016/S0006-8993(03)02284-4.CrossRefPubMed
15.
De Ciantis PD, Yashpal K, Henry J, Singh G: Characterization of a rat model of metastatic prostate cancer bone pain. J Pain Res. 2010, 3: 213-221.PubMedCentralPubMed
16.
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. 10.1016/j.bbrc.2006.04.186.CrossRefPubMed
17.
Zhao J, Pan HL, Li TT, Zhang YQ, Wei JY, Zhao ZQ: The sensitization of peripheral C-fibers to lysophosphatidic acid in bone cancer pain. Life Sci. 2010, 87: 120-125. 10.1016/j.lfs.2010.05.015.CrossRefPubMed
18.
Tong W, Wang W, Huang J, Ren N, Wu SX, Li YQ: Spinal high-mobility group box 1 contributes to mechanical allodynia in a rat model of bone cancer pain. Biochem Biophys Res Commun. 2010, 395: 572-576. 10.1016/j.bbrc.2010.04.086.CrossRefPubMed
19.
Svensson CI, Medicherla S, Malkmus S, Jiang Y, Ma JY, Kerr I, Brainin-Mattos J, Powell HC, Luo ZD, Chakravarty S, Dugar S, Higgins LS, Protter AA, Yaksh TL: Role of p38 mitogen activated protein kinase in a model of osteosarcoma-induced pain. Pharmacol Biochem Behav. 2008, 90: 664-675. 10.1016/j.pbb.2008.05.016.CrossRefPubMed
20.
Lee Y, Pai M, Brederson JD, Wilcox D, Hsieh G, Jarvis MF, Bitner RS: Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord. Mol Pain. 2011, 7: 39-10.1186/1744-8069-7-39.PubMedCentralCrossRefPubMed
21.
22.
23.
Mantyh PW: Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci. 2006, 7: 797-809.CrossRefPubMed
24.
Woodward EJ, Coleman RE: Prevention and treatment of bone metastases. Curr Pharm Des. 2010, 16: 2998-3006. 10.2174/138161210793563581.CrossRefPubMed
25.
26.
Mei XP, Zhang H, Wang W, Wei YY, Zhai MZ, Wang W, Xu LX, Li YQ: Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain. J Neuroinflammation. 2011, 8: 6-10.1186/1742-2094-8-6.PubMedCentralCrossRefPubMed
27.
Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MC, Clohisy DR, Mantyh PW: Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience. 2000, 98: 585-598. 10.1016/S0306-4522(00)00110-X.CrossRefPubMed
28.
Manjavachi MN, Motta EM, Marotta DM, Leite DF, Calixto JB: Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice. Pain. 2010, 151: 345-355. 10.1016/j.pain.2010.07.018.CrossRefPubMed
29.
Gao YJ, Zhang L, Ji RR: Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1. Glia. 2010, 58: 1871-1880. 10.1002/glia.21056.PubMedCentralCrossRefPubMed
30.
Gu X, Zheng Y, Ren B, Zhang R, Mei F, Zhang J, Ma Z: Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model. Mol Pain. 2010, 6: 64-10.1186/1744-8069-6-64.PubMedCentralCrossRefPubMed
31.
Yao M, Chang XY, Chu YX, Yang JP, Wang LN, Cao HQ, Liu MJ, Xu QN: Antiallodynic effects of propentofylline Elicited by interrupting spinal glial function in a rat model of bone cancer pain. J Neurosci Res. 2011, 89: 1877-1886. 10.1002/jnr.22711.CrossRefPubMed
32.
Muir WW: NMDA receptor antagonists and pain: ketamine. Vet Clin North Am Equine Pract. 2010, 26: 565-578. 10.1016/j.cveq.2010.07.009.CrossRefPubMed
33.
Guo RX, Zhang M, Liu W, Zhao CM, Cui Y, Wang CH, Feng JQ, Chen PX: NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance. Neurosci Lett. 2009, 467: 95-99. 10.1016/j.neulet.2009.10.013.CrossRefPubMed
34.
Zhang RX, Liu B, Li A, Wang L, Ren K, Qiao JT, Berman BM, Lao L: Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. Neuroscience. 2008, 154: 1533-1538. 10.1016/j.neuroscience.2008.04.072.PubMedCentralCrossRefPubMed
35.
Yanagisawa Y, Furue H, Kawamata T, Uta D, Yamamoto J, Furuse S, Katafuchi T, Imoto K, Iwamoto Y, Yoshimura M: Bone cancer induces a unique central sensitization through synaptic changes in a wide area of the spinal cord. Mol Pain. 2010, 6: 38-10.1186/1744-8069-6-38.PubMedCentralCrossRefPubMed
36.
Gu X, Zhang J, Ma Z, Wang J, Zhou X, Jin Y, Xia X, Gao Q, Mei F: The role of N-methyl-D-aspartate receptor subunit NR2B in the spinal cord in cancer pain. Eur J Pain. 2010, 14: 496-502. 10.1016/j.ejpain.2009.09.001.CrossRefPubMed
37.
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: 1061-1095. 10.1128/MMBR.00025-06.PubMedCentralCrossRefPubMed
38.
Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983, 16: 109-110. 10.1016/0304-3959(83)90201-4.CrossRefPubMed
39.
Liu S, Liu WT, Liu YP, Dong HL, Henkemeyer M, Xiong LZ, Song XJ: Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents. Cancer Res. 2011, 71: 4392-4402. 10.1158/0008-5472.CAN-10-3870.CrossRefPubMed
40.
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. 10.1213/01.ane.0000226100.46866.ea.CrossRefPubMed
Metadata
Title
Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats
Authors
Xiao-Wei Wang
Shan Hu
Qi-Liang Mao-Ying
Qian Li
Chang-Jiang Yang
Hui Zhang
Wen-Li Mi
Gen-Cheng Wu
Yan-Qing Wang
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2012
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/1756-6606-5-21

Other articles of this Issue 1/2012

Molecular Brain 1/2012 Go to the issue

Short report

The Brugada syndrome mutation A39V does not affect surface expression of neuronal rat Cav1.2 channels

Research

Wnt proteins regulate acetylcholine receptor clustering in muscle cells

Research

Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity

Research

Barrel cortical neurons and astrocytes coordinately respond to an increased whisker stimulus frequency

Review

Caspases in synaptic plasticity

Review

The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB