title: JNK in spinal cord facilitates bone cancer pain in rats through modulation of CXCL1.
abstract: 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.
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Wuhan Medical and Health Center for Women and Children, Wuhan, 430015, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Du
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. zrg27@163.com.
authors.forename: Rui-Guang
authors.initials: RG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000150:complications / Q000378:metabolism*; D000072716:Cancer Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism*; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases
keywords: SP600125; bone cancer pain; c-Jun N-terminal kinase; chemokine (C-X-C motif) ligand 1; neural-glial interaction
references.citation: Brain Res Dev Brain Res. 2001 May 31;128(1):77-81
references.pmid: 11356265
references.citation: Mol Pain. 2008 Sep 24;4:38
references.pmid: 18816377
references.citation: Neuroscience. 2008 Jul 17;154(4):1533-8
references.pmid: 18554806
references.citation: J Neurosci Res. 1998 Aug 1;53(3):368-76
references.pmid: 9698165
references.citation: J Neuroinflammation. 2014 Mar 01;11:38
references.pmid: 24580964
references.citation: Microbiol Mol Biol Rev. 2006 Dec;70(4):1061-95
references.pmid: 17158707
references.citation: Pain. 2013 Dec;154 Suppl 1:S54-62
references.pmid: 23916671
references.citation: Mol Pain. 2009 May 28;5:26
references.pmid: 19476648
references.citation: Pain. 2013 Jun;154(6):917-26
references.pmid: 23582155
references.citation: J Neuroinflammation. 2014 Apr 16;11:75
references.pmid: 24735601
references.citation: J Neurosci. 2007 Nov 7;27(45):12396-406
references.pmid: 17989304
references.citation: Pain. 2013 Oct;154(10):2185-97
references.pmid: 23831863
references.citation: Dev Neurosci. 2003 Mar-Aug;25(2-4):279-90
references.pmid: 12966224
references.citation: Exp Neurol. 2009 Sep;219(1):146-55
references.pmid: 19445931
references.citation: Neuropharmacology. 2007 Mar;52(3):708-15
references.pmid: 17084420
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20151-8
references.pmid: 18083844
references.citation: Pain. 2002 Mar;96(1-2):129-40
references.pmid: 11932069
references.citation: J Neurosci Res. 2005 Oct 1;82(1):51-62
references.pmid: 16047385
references.citation: Brain Res. 2003 Apr 25;970(1-2):195-204
references.pmid: 12706261
references.citation: Neurobiol Dis. 2006 May;22(2):312-22
references.pmid: 16472549
references.citation: Gac Med Mex. 2013 Mar-Apr;149(2):204-11
references.pmid: 23652187
references.citation: J Neurosci. 2006 Mar 29;26(13):3551-60
references.pmid: 16571763
references.citation: J Immunol. 1997 Mar 15;158(6):2882-90
references.pmid: 9058825
references.citation: Pain. 2014 Jul;155(7):1346-55
references.pmid: 24727346
references.citation: Pain. 2010 Feb;148(2):309-19
references.pmid: 20022176
references.citation: Mol Brain. 2012 Jun 09;5:21
references.pmid: 22681856
references.citation: Pain. 1988 Jan;32(1):77-88
references.pmid: 3340425
references.citation: J Neurosci. 2009 Apr 1;29(13):4096-108
references.pmid: 19339605
references.citation: Neurosci Lett. 2008 Jun 6;437(3):180-3
references.pmid: 18455869
references.citation: Pain. 2010 Jan;148(1):148-57
references.pmid: 19945222
references.citation: Neurosci Bull. 2012 Apr;28(2):155-64
references.pmid: 22466126
references.citation: Acta Pharmacol Sin. 2014 Mar;35(3):339-50
references.pmid: 24487964
references.citation: Brain. 2005 May;128(Pt 5):1003-15
references.pmid: 15774504
references.citation: Biochem Biophys Res Commun. 2006 Jul 14;345(4):1292-8
references.pmid: 16725112