Abstract
BackgroundBone cancer pain (BCP) is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies show several chemokines (for example, CCL2, CXCL10) in the spinal cord are involved in the pathogenesis of BCP. Here we investigated whether and how spinal CXCL1 contributes to BCP.MethodsMouse prostate tumor cell line, RM-1 cells were intramedullary injected into the femur to induce BCP. The mRNA expression of CXCL1 and CXCR2 was detected by quantitative real-time PCR. The protein expression and distribution of CXCL1, NFκB, and CXCR2 was examined by immunofluorescence staining and western blot. The effect of CXCL1 neutralizing antibody, NFκB antagonist, and CXCR2 antagonist on pain hypersensitivity was checked by behavioral testing.ResultsIntramedullary injection of RM-1 cells into the femur induced cortical bone damage and persistent (>21 days) mechanical allodynia and heat hyperalgesia. Tumor cell inoculation also produced CXCL1 upregulation in activated astrocytes in the spinal cord for more than 21 days. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody at 7 days after inoculation attenuated mechanical allodynia and heat hyperalgesia. In cultured astrocytes, TNF-α induced robust CXCL1 expression, which was dose-dependently decreased by NFκB inhibitor. Furthermore, inoculation induced persistent NFκB phosphorylation in spinal astrocytes. Intrathecal injection of NFκB inhibitor attenuated BCP and reduced CXCL1 increase in the spinal cord. Finally, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after inoculation. Inhibition of CXCR2 by its selective antagonist SB225002 attenuated BCP.ConclusionNFκB mediates CXCL1 upregulation in spinal astrocytes in the BCP model. In addition, CXCL1 may be released from astrocytes and act on CXCR2 on neurons in the spinal cord and be involved in the maintenance of BCP. Inhibition of the CXCL1 signaling may provide a new therapy for BCP management.
Highlights
Bone cancer pain (BCP) is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases
As the biological effects of chemokines are mediated via interaction with its G protein-coupled receptor, and Chemokine CXC motif receptor 2 (CXCR2) is the primary receptor of Chemokine CXC motif ligand 1 (CXCL1), we further investigated the expression and distribution of CXCR2 in the spinal cord and the antinociceptive effect of CXCR2 antagonist
Pain behavioral studies showed that tumor cell inoculation produced an obvious pain hypersensitivity, which was characterized by heat hyperalgesia and mechanical allodynia in the right hindpaws of inoculated mice
Summary
Bone cancer pain (BCP) is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies show several chemokines (for example, CCL2, CXCL10) in the spinal cord are involved in the pathogenesis of BCP. Tissue injury/inflammation, nerve injury, and tumor growth can induce glial cells (astrocytes and microglia) to be reactive and release a variety of inflammatory mediators, including proinflammatory cytokines and chemokines, which may augment the nociceptive signals in the spinal cord [5,6,7,8]. Recent studies have shown that some chemokines in the spinal cord are involved in BCP. CCL2 expression is increased in spinal astrocytes and microglia in mice with BCP [9]. Tumor cell inoculation induces the increases of CXCL10 and its major receptor CXCR3 in the spinal cord. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevents the development of BCP and microglial activation [11]
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