Positive feedback regulation between microRNA‐132 and CREB in spinal cord contributes to bone cancer pain in mice. (26th February 2016)

• Record Type: Journal Article
• Authors: Hou, B.; Cui, X.; Liu, Y.; Zhang, W.; Liu, M.; Sun, Y.E.; Ma, Z.; Gu, X.
• Is Part Of: European journal of pain. Volume 20:Number 8(2016)
• Page Start: 1299
• Page End: 1308
• Publication Date: 2016-02-26
• Subjects: Pain -- Periodicals; Pain -- Treatment -- Periodicals; Pain -- Physiological aspects -- Periodicals; 616.0472
• DOI: 10.1002/ejp.854
• Languages: English
• ISSNs: 1090-3801

Abstract

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.