Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Abstract

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 na€ ıve 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. Keywords: astrocytes, bone cancer pain, chemokine, mitogenactivated protein kinase, microglia, neuroinflammation. Bone cancer pain (BCP) caused by primary tumors or bone metastases is the most common source of moderate and severe cancer pain, which not only makes patients less confident to receive therapeutic plan but also discourages tumor-burdened people from desiring to live (Knopp et al. 2011). With effective treatment strategies depending on a better understanding of BCP, intensive studies of underlying pathogenic mechanisms of BCP and development of novel analgesic targets are highly anticipated in the basic and clinical research communities.Following local inoculation of primary or metastatic bone tumor in the bone microenvironment, cellular and neurochemical alterations take place abundantly in the spinal cord, triggering hyperalgesic behaviors (Medhurst et al. 2002). In this complex pathophysiologic process, glial cells (especially astrocytes and microglia) react and release various proinflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b) and IL-6, which enhance central sensitization and thus evoking pain hypersensitivity (Falk and Dickenson 2014). Indeed, inhibiting functional activation of astrocytes and microglia at the spinal level is sufficient to suppress BCP and these glia-derived mediators Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially che...

CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

“…The results suggested that microglia might also be involved in CXCL12/CXCR4-mediated cancer pain processing in the CNS. Furthermore, in the same model, it was found that TCI treatment increased the phosphorylation of MAPK pathways and the production of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the lumbar spinal cord (Hu et al, 2015). The blockade of CXCL12/CXCR4 axis by AMD3100 or CXCL12 neutralizing antibody or MAPK pathways (by ERK inhibitor [U0126], JNK inhibitor [SP600125], or p38 inhibitor [SB503580]) reversed persistent pain and downregulated the production of these cytokines in a rat bone cancer model.…”

“…In intact animals, a single intrathecal injection of CXCL12 produced transient mechanical allodynia, and such allodynia was reversed by pretreatment of CXCR4 neutralizing antibody (12G5) (Reaux-Le Goazigo et al, 2012) or CXCR4 antagonist (AMD3100) intrathecally (Hu et al, 2015). Central mechanisms for CXCL12/CXCR4 in chronic pain are also delineated in Figure 2.…”

“…Multiple molecular pain pathways might account for the central pronociceptive property of CXCL12/CXCR4 axis. In normal rats, the intrathecal injection of CXCL12 increased the phosphorylation of ERK, JNK, and p38 pathways in the spinal dorsal horn, and such activation was reversed by the pretreatment of AMD3100 (Hu et al, 2015). Central MAPK pathways are essential for the development and maintenance of various types of pathological pain in a cell type-specific manner.…”

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

“…Astrocyte activation has been shown to increase in bone cancer mice (Pevida et al, 2014) and both astrocytes and microglia have been shown to contribute to bone cancer pain in a rat model (Mao-Ying et al, 2012), but hyperactivation of these cells does not influence the maintenance of cancer pain hypersensitivity (Zhang et al, 2005). Finally, it has been recently reported that CXCL12 released from astrocytes acts on CXCR4 expressing microglia and astrocytes to activate them and contributes to the development of cancer pain (Hu et al, 2015). Because there is still controversy regarding the role of astrocytes in cancer pain and because there are no studies that have examined the potential role of spinal cord aromatase in cancer pain, we examined both astrocyte and aromatase expression in both a painful and nonpainful model of hindpaw bone cancer pain.…”

CXCR3: Latest evidence for the involvement of chemokine signaling in bone cancer pain

“…Nevertheless, a previous study suggested that spinal CCL5 was related to BCP, for the reason that intrathecal injection of a CCL5 neutralizing antibody was able to prevent tumoral hyperalgesia (Hang et al, 2013). (4) In BCP rats, increased expressions of CXCL12 and CXCR4 in the spinal cord were detected, and CXCL12/CXCR4 signaling-mediated neuronal sensitization and glial activation were crucial for the development and maintenance of BCP (Hu et al, 2014). (5) CXCL10 and its receptor CXCR3 were up-regulated in the spinal cord of BCP rats.…”