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Positive feedback regulation between micro RNA ‐132 and CREB in spinal cord contributes to bone cancer pain in mice
Author(s) -
Hou B.,
Cui X.,
Liu Y.,
Zhang W.,
Liu M.,
Sun Y.E.,
Ma Z.,
Gu X.
Publication year - 2016
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.854
Subject(s) - creb , medicine , spinal cord , cancer research , neuroscience , biology , transcription factor , gene , genetics
Background cAMP response element‐binding protein ( CREB )‐dependent gene expression plays an important role in central sensitization. CREB ‐regulated transcription coactivator 1 ( CRTC 1) dramatically increase CREB ‐mediated transcriptional activity. micro RNA ‐132 (miR‐132), which is highly CREB ‐responsive, functions downstream from CREB / CRTC 1 to mediate activity‐dependent synaptic plasticity and in turn loops back to amplify CREB / CRTC 1 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/He NC rlVr mice to induce bone cancer pain. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CREB ‐si RNA or miR‐132 antisense locked nucleic acid ( LNA ), respectively, on nociceptive behaviours and on the activity of CREB / CRTC 1 signalling. Results Intramedullary inoculation of osteosarcoma cells resulted in up‐regulation of spinal p‐ CREB , CRTC 1 and CREB ‐target genes ( NR 2B and miR‐132). Repeated intrathecal administration with Adenoviruses expressing CREB ‐si RNA or miR‐132 LNA ‐ AS , respectively, attenuated bone cancer‐evoked pain behaviours, reduced the activity of CREB / CRTC 1 signalling and down‐regulated CREB ‐target gene NR 2B expression in spinal cord. Conclusions These findings suggest that activation of spinal CREB / CRTC 1 signalling may play an important role in bone cancer pain. Interruption to the positive feedback regulation between CREB / CRTC 1 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 / CRTC 1 and its target gene miR‐132 in spinal cord plays an important role in bone cancer pain.