Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.
Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons.
['Chao|Yu-Chieh|YC|', 'Xie|Fang|F|', 'Li|Xueyang|X|', 'Guo|Ruijuan|R|', 'Yang|Ning|N|', 'Zhang|Chen|C|', 'Shi|Rong|R|', 'Guan|Yun|Y|', 'Yue|Yun|Y|', 'Wang|Yun|Y|']
D000701:Analgesics, Opioid D000818:Animals D019208:Brain-Derived Neurotrophic Factor D000073398:Demethylation D005727:Ganglia, Spinal D005786:Gene Expression Regulation D008297:Male D009020:Morphine D009474:Neurons D010146:Pain D051381:Rats D017207:Rats, Sprague-Dawley
Dorsal root ganglion Brain-derived neurotrophic factor Epigenetics Opioid-induced hyperalgesia