Positive feedback regulation between micro<scp>RNA</scp>‐132 and <scp>CREB</scp> in spinal cord contributes to bone cancer pain in mice

Abstract

BACKGROUND: cAMP response element-binding protein (CREB)-dependent gene expression plays an important role in central sensitization. CREB-regulated transcription coactivator 1 (CRTC1) dramatically increase CREB-mediated transcriptional activity. microRNA-132 (miR-132), which is highly CREB-responsive, functions downstream from CREB/CRTC1 to mediate activity-dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signalling. This study aimed to investigate the positive feedback regulation between miR-132 and CREB in spinal cord in the maintenance of bone cancer pain. METHODS: Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeNCrlVr mice to induce bone cancer pain. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CREB-siRNA or miR-132 antisense locked nucleic acid (LNA), respectively, on nociceptive behaviours and on the activity of CREB/CRTC1 signalling. RESULTS: Intramedullary inoculation of osteosarcoma cells resulted in up-regulation of spinal p-CREB, CRTC1 and CREB-target genes (NR2B and miR-132). Repeated intrathecal administration with Adenoviruses expressing CREB-siRNA or miR-132 LNA-AS, respectively, attenuated bone cancer-evoked pain behaviours, reduced the activity of CREB/CRTC1 signalling and down-regulated CREB-target gene NR2B expression in spinal cord. CONCLUSIONS: These findings suggest that activation of spinal CREB/CRTC1 signalling may play an important role in bone cancer pain. Interruption to the positive feedback regulation between CREB/CRTC1 and its target gene miR-132 can effectively relieved the bone cancer-induced mechanical allodynia and spontaneous pain. WHAT DOES THIS STUDY ADD?: The positive feedback regulation between CREB/CRTC1 and its target gene miR-132 in spinal cord plays an important role in bone cancer pain.