CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats.
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 CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK-mediated mechanism. In naïve rats, a single intrathecal administration of CXCL12 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 CXCR4 inhibitor AMD3100. This CXCL12-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 CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation-induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4-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.
Department of Pain Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
Xue-Ming
XM
Hu
Yan-Nan
YN
Liu
Hai-Long
HL
Zhang
Shou-Bin
SB
Cao
Ting
T
Zhang
Li-Ping
LP
Chen
Wen
W
Shen
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000633:toxicity; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007278:Injections, Spinal; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D020928:Mitogen-Activated Protein Kinases
astrocytes; bone cancer pain; chemokine; microglia; mitogen-activated protein kinase; neuroinflammation