Methylation of glucocorticoid receptor gene promoter modulates morphine dependence and accompanied hypothalamus-pituitary-adrenal axis dysfunction.
Previous studies demonstrated that dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis played an important role in morphine dependence. Nonetheless, the molecular mechanism underlying morphine-induced HPA axis dysfunction and morphine dependence remains unclear. In the current study, 5'-aza-2'-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases (DNMTs), was used to examine the effects of glucocorticoid receptor (GR) promoter 17methylation on chronic morphine-induced HPA axis dysfunction and behavioral changes in rats and the underlying mechanism. Our results showed that chronic but not acute morphine downregulated the expression of nuclear GR protein and GR exon 17variant mRNA, and upregulated the methylation of GR 17exon promoter in the hippocampus of rats. Meanwhile, 5-aza per se had no effect on observed molecular and behavior change. In contrast, pretreatment of 5-aza into rat hippocampus reversed chronic morphine-induced hypermethylation of GR 17promoter and decrease in GR expression. Moreover, pretreatment of 5-aza attenuated chronic morphine-enhanced HPA axis reactivity and the naloxone-precipitated somatic signs in morphine-dependent rats. Our results suggest that chronic morphine induced hypermethylation of GR 17promoter, which then downregulated the expression of hippocampal GR, and was thus involved in chronic morphine-induced dysfunction of the HPA axis and the modulation of morphine dependence. Moreover, chronic morphine-induced hypermethylation of GR 17promoter may be at least partially due to the increase in hippocampal DNMT 1 expression and its binding at GR 17promoter in the rat hippocampus. © 2016 Wiley Periodicals, Inc.
College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.
Jie
J
Zhu
Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Feng
F
Zhu
Northwest University of Politics and Law School of Police, Xi'an, Shaanxi, People's Republic of China.
Na
N
Zhao
College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.|Reproductive Medicine Center, Maternal and Child Health Hospital of Shaanxi Province & Northwest Women's and Children's Hospital, Xi'an, Shaanxi, People's Republic of China.
Xin
X
Mu
College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.
Pingping
P
Li
Department of Psychiatry, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Wei
W
Wang
School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.
Jian
J
Liu
Department of Psychiatry, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Xiancang
X
Ma
D000818:Animals; D001483:Base Sequence; D019175:DNA Methylation / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D009021:Morphine Dependence / Q000235:genetics / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
D011965:Receptors, Glucocorticoid
AB_10711417; AB_2107448; AB_2139612; AB_2155786; AB_300438; DNA methylation; glucocorticoid receptor; hypothalamus-pituitary-adrenal axis; morphine dependence