HIF-1α/MMP-9 promotes spinal cord central sensitization in rats with bone cancer pain

Bone cancer pain (BCP) is one of the most prevalent and serious symptoms of patients with cancer. Currently, the medical interventions used for the treatment of BCP do not act with optimal safety and efficacy. In this study, we appraised whether the hypoxia-inducible factor 1α (HIF-1α)/metalloproteinase-9 (MMP9) axis activates the PI3K/AKT pathway, resulting in elevated spinal cord central sensitization and aggravated BCP. BCP rats were established by tibial injection of Walker 256 cells, followed by different interventions in rats using HIF-1ɑ inhibitor LW6 or antibody treatments. After treatment with LW6 or antibody against HIF-1α, central sensitization in the spinal cord tissues of rats was inhibited, and pain perception in rats was reduced. Moreover, the activation of glial cells in the spinal cord tissues was ameliorated. The expression of MMP9 was remarkably suppressed in spinal cord tissues after inhibition of HIF-1ɑ activity, and the activity of the PI3K/AKT signaling pathway was inhibited. Further activation of MMP9 expression suppressed the alleviating effect of HIF-1ɑ inhibitor LW6 or antibody on pain perception in rats inoculated with tumors. Taken together, our studies suggest a HIF-1α/MMP9-mediated activation of PI3K/AKT in the spinal cord tissues, resulting in increased pain perception in a rat model with BCP.