title: Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Chao
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
authors.forename: Xueyang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Anesthesiology, Beijing Hospital, Peking University Health Science Center, Beijing, 100730, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. Electronic address: yueyun@hotmail.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. Electronic address: wangyun129@ccmu.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D000073398:Demethylation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D019208:Brain-Derived Neurotrophic Factor; D009020:Morphine
keywords: Brain-derived neurotrophic factor; Dorsal root ganglion; Epigenetics; Opioid-induced hyperalgesia