title: Histone deacetylase inhibitor-induced emergence of synaptic δ-opioid receptors and behavioral antinociception in persistent neuropathic pain.
abstract: The efficacy of opioids in patients with chronic neuropathic pain remains controversial. Although activation of δ-opioid receptors (DORs) in the brainstem reduces inflammation-induced persistent hyperalgesia, it is not effective under persistent neuropathic pain conditions and these clinical problems remain largely unknown. In this study, by using a chronic constriction injury (CCI) of the sciatic nerve in rats, we found that in the brainstem nucleus raphe magnus (NRM), DORs emerged on the surface membrane of central synaptic terminals on day 3 after CCI surgery and disappeared on day 14. Histone deacetylase (HDAC) inhibitors microinjected into the NRM in vivo increased the level of synaptosomal DOR protein and NRM infusion of DOR agonists producing an antinociceptive effect in a nerve growth factor (NGF) signaling-dependent manner. In vitro, in CCI rat slices incubated with HDAC inhibitors, DOR agonists significantly inhibited EPSCs. This effect was blocked by tyrosine receptor kinase A antagonists. Chromatin immunoprecipitation analysis revealed that NRM infusion of HDAC inhibitors in CCI rats increased the level of histone H4 acetylation at Ngf gene promoter regions. NGF was infused into the NRM or incubated CCI rat slices drove DORs to the surface membrane of synaptic terminals. Taken together, epigenetic upregulation of NGF activity by HDAC inhibitors in the NRM promotes the trafficking of DORs to pain-modulating neuronal synapses under neuropathic pain conditions, leading to δ-opioid analgesia. These findings indicate that therapeutic use of DOR agonists combined with HDAC inhibitors might be effective in chronic neuropathic pain managements.
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Tao
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: zhizhang@ustc.edu.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Brain Function and Disease of Chinese Academy of Science and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: jinyan@ustc.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D065846:Nucleus Raphe Magnus / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D012584:Sciatic Nerve / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D000700:Analgesics; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D017465:Receptors, Opioid, delta; C012589:trichostatin A
keywords: antinociception; histone deacetylase; neuropathic pain; δ-opioid receptors