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Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats
Author(s) -
Hu XueMing,
Liu YanNan,
Zhang HaiLong,
Cao ShouBin,
Zhang Ting,
Chen LiPing,
Shen Wen
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12985
Subject(s) - neuroinflammation , proinflammatory cytokine , microglia , mapk/erk pathway , chemokine , cancer research , signal transduction , bone cancer , medicine , immunology , microbiology and biotechnology , biology , inflammation , osteosarcoma
The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain ( BCP ). Our previous study showed that spinal CXCL 12 from astrocytes mediates BCP generation by binding to CXCR 4 in both astrocyters and microglia. Here, we verified that CXCL 12/ CXCR 4 signaling contributed to BCP through a MAPK ‐mediated mechanism. In naïve rats, a single intrathecal administration of CXCL 12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal‐regulated kinase, p38, and c‐Jun N‐terminal kinase), which could be partially prevented by pre‐treatment with CXCR 4 inhibitor AMD 3100. This CXCL 12‐induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up‐regulation of CXCL 12 and CXCR 4, activation of glial cells, phosphorylation of MAPK s, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation‐induced behavioral and neurochemical alterations were all suppressed by blocking CXCL 12/ CXCR 4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL 12/ CXCR 4‐induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia‐derived neuroinflammation.Following tumor cell inoculation, chemokine CXCL12 from astrocytes spreads around the spinal environment, resulting in functional activation of CXCR4‐expressing astrocytes and microglia. Once glia are activated, they may initiate MAPK (mitogen‐activated protein kinase) pathways, and subsequently produce proinflammatory cytokines and chemokines. Among them, CXCL12 could reinforce the astrocytic and microglial activation in autocrine and paracrine manners. Such positive feedback loops sustain perseverant neuroinflammation, facilitate glial activation, and finally lead to bone cancer pain. IL = interleukin; TNF = tumor necrosis factor.