1. G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury.
- Author
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Liang, Lingli, Zhao, Jian-Yuan, Gu, Xiyao, Wu, Shaogen, Mo, Kai, Xiong, Ming, Marie Lutz, Brianna, Bekker, Alex, and Tao, Yuan-Xiang
- Subjects
CREB protein ,OPIOID receptors ,SENSORY neurons ,PERIPHERAL nerve injuries ,DORSAL root ganglia ,GENE expression - Abstract
Neuropathic pain, a distressing and debilitating disorder, is still poorly managed in clinic. Opioids, like morphine, remain the mainstay of prescribed medications in the treatment of this disorder, but their analgesic effects are highly unsatisfactory in part due to nerve injury-induced reduction of opioid receptors in the first-order sensory neurons of dorsal root ganglia. G9a is a repressor of gene expression. We found that nerve injury-induced increases in G9a and its catalyzed repressive marker H3K9m2 are responsible for epigenetic silencing of
Oprm1 ,Oprk1 , andOprd1 genes in the injured dorsal root ganglia. Blocking these increases rescued dorsal root gangliaOprm1 ,Oprk1 , andOprd1 gene expression and morphine or loperamide analgesia and prevented the development of morphine or loperamide-induced analgesic tolerance under neuropathic pain conditions. Conversely, mimicking these increases reduced the expression of three opioid receptors and promoted the mu opioid receptor-gated release of primary afferent neurotransmitters. Mechanistically, nerve injury-induced increases in the binding activity of G9a and H3K9me2 to theOprm1 gene were associated with the reduced binding of cyclic AMP response element binding protein to theOprm1 gene. These findings suggest that G9a participates in the nerve injury-induced reduction of theOprm1 gene likely through G9a-triggered blockage in the access of cyclic AMP response element binding protein to this gene. [ABSTRACT FROM AUTHOR]- Published
- 2016
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