EphrinBs/EphBs Signaling Is Involved in Modulation of Spinal Nociceptive Processing through a Mitogen-activated Protein Kinases-dependent Mechanism

Ruan, Jiaping; Zhang, Hongxing; Lu, Xianfu; Liu, Yuepeng; Cao, Jun‐Li

doi:10.1097/aln.0b013e3181d3e0df

Cited by 50 publications

(53 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We speculate that species differences may account for these differences as we examined pain behaviors in mice and the previous study used rats. Indeed, in other study, the activation of spinal EphB receptors by using another reagent, ephrinB1-Fc, also produced thermal hyperalgesia and mechanical allodynia in mice (Ruan et al, 2010;Yu et al, 2012). Nevertheless, other factors, such as the use of different doses and different nociception tests, also potentially contributed to the discrepancies between our results and those of the previous study.…”

Section: Ephrinb-ephb Signaling and Paincontrasting

confidence: 75%

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

et al. 2015

View full text Add to dashboard Cite

Section: Ephrinb-ephb Signaling and Paincontrasting

confidence: 75%

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

et al. 2015

View full text Add to dashboard Cite

“…or i.t. injection of ephrinB1-Fc [33], [34]. Pre- or post-treatment with MEK inhibitor prevented or reversed hyperalgesia induced by i.pl.…”

Section: Resultsmentioning

confidence: 97%

PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs

Zhou

et al. 2012

PLoS ONE

Self Cite

View full text Add to dashboard Cite

There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

show abstract

“…Serving as key nociceptive signals in glial cells, MAPKs are activated and address central sensitization under pain states (Ji et al 2009(Ji et al , 2013Ruan et al 2010). Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially chemokine receptors (e.g., CX3CR1 and CXCR2) (Gao and Ji 2010).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

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

Liu

Zhang

et al. 2015

Journal of Neurochemistry

View full text Add to dashboard Cite

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...

show abstract

EphrinBs/EphBs Signaling Is Involved in Modulation of Spinal Nociceptive Processing through a Mitogen-activated Protein Kinases-dependent Mechanism

Abstract: These results demonstrated that activation of MAPKs contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

Cited by 50 publications

References 66 publications

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs

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

Contact Info

Product

Resources

About