title: Brainstem brain-derived neurotrophic factor signaling is required for histone deacetylase inhibitor-induced pain relief.
abstract: Our previous study demonstrated that persistent pain can epigenetically suppress the transcription of Gad2 [encoding glutamic acid decarboxylase 65 (GAD65)] and consequently impair the inhibitory function of GABAergic synapses in central pain-modulating neurons. This contributes to the development of persistent pain sensitization. Histone deacetylase (HDAC) inhibitors increased GAD65 activity considerably, restored GABA synaptic function, and rendered sensitized pain behavior less pronounced. However, the molecular mechanisms by which HDAC regulates GABAergic transmission through GAD65 under pain conditions are unknown. This work showed that HDAC inhibitor-induced increases in colocalization of GAD65 and synaptic protein synapsin I on the presynaptic axon terminals of the nucleus raphe magnus (NRM) were blocked by a TrkB receptor antagonist K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], indicating that BDNF-TrkB signaling may be required in GAD65 modulation of GABA synaptic function. At the brain-derived neurotrophic factor (BDNF) promoter, HDAC inhibitors induced significant increases in H3 hyperacetylation, consistent with the increase in BDNF mRNA and total proteins. Although exogenous BDNF facilitated GABA miniature inhibitory postsynaptic currents and GAD65 accumulation in NRM neuronal synapses in normal rats, it failed to do so in animals subjected to persistent inflammation. In addition, blockade of the TrkB receptor with K252a has no effect on miniature inhibitory postsynaptic currents and synaptic GAD65 accumulation under normal conditions. In addition, the analgesic effects of HDAC inhibitors on behavior were blocked by NRM infusion of K252a. These findings suggest that BDNF-TrkB signaling is required for drugs that reverse the epigenetic effects of chronic pain at the gene level, such as HDAC inhibitors.
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors: Wenjuan
authors: W
authors: Tao
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors: Quan
authors: Q
authors: Chen
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors: Lu
authors: L
authors: Wang
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors: Wenjie
authors: W
authors: Zhou
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors: Yunping
authors: Y
authors: Wang
authors: Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China zhizhang@ustc.edu.cn.
authors: Zhi
authors: Z
authors: Zhang
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D008297:Male; D065846:Nucleus Raphe Magnus / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D000077337:Vorinostat; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000700:Analgesics; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D026121:Indole Alkaloids; D016704:Synapsins; C012589:trichostatin A; D005680:gamma-Aminobutyric Acid; D000077337:Vorinostat; C049985:staurosporine aglycone; D020813:Receptor, trkB; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2