title: Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits.
abstract: The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and the Department of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui 241000, China.
authors: Wenjuan
authors: W
authors: Tao
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and.
authors: Quan
authors: Q
authors: Chen
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and.
authors: Wenjie
authors: W
authors: Zhou
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and.
authors: Yunping
authors: Y
authors: Wang
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and.
authors: Lu
authors: L
authors: Wang
authors: From the Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China and zhizhang@ustc.edu.cn.
authors: Zhi
authors: Z
authors: Zhang
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D019706:Excitatory Postsynaptic Potentials; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D065846:Nucleus Raphe Magnus / Q000503:physiopathology*; D010146:Pain / Q000235:genetics / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism; D018091:Receptors, AMPA / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D009435:Synaptic Transmission; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011493:Protein Kinase C; D012333:RNA, Messenger; D020813:Receptor, trkB; D018091:Receptors, AMPA; D010738:Type C Phospholipases
keywords: BDNF; Epigenetics; GluA1; Pain