title: Suberoylanilide hydroxamic acid prevents downregulation of spinal glutamate transporter-1 and attenuates spinal nerve ligation-induced neuropathic pain behavior.
abstract: Glutamate transporter-1 (GLT-1) reduction causes dysregulation of excitatory-inhibitory balance, contributing toward neuropathic pain development. However, the mechanisms underlying GLT-1 downregulation are still unclear. Histone acetylation plays a pivotal role in the regulation of gene expression. We sought to examine the contribution of histone acetylation on pain hypersensitivity and GLT-1 downregulation in neuropathic pain development. Histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was intrathecally infused to rats through osmotic pumps from -5 days to 7 days after spinal nerve ligation (SNL). Behavioral tests indicated that SAHA could significantly prevent SNL-induced mechanical allodynia and thermal hyperalgesia. The effect was dose related and lasted to 10 days after SNL when the SAHA infusion was stopped on day 7. Immunohistochemistry, western blot, and real-time reverse transcription PCR analysis showed that SAHA significantly prevented SNL-induced downregulation of GLT-1 in the spinal dorsal horn. In addition, SNL-induced weakened acetylation of histone H3 (AcH3) was significantly inhibited by SAHA. Immunofluorescent histochemistry showed that both GLT-1 and AcH3 had high expressions in the dorsal horn. Double staining indicated that several GLT-1-positive cells were colocalized with AcH3. Our data provide evidence that histone deacetylation may contribute toward the loss of GLT-1 and this could be a new consideration for the development of more effective strategies for treating neuropathic pain.
authors.affiliation: aState Key Laboratory of Military Stomatology, Department of Anesthesiology, School of Stomatology, the Fourth Military Medical University, Xi'an bDepartment of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Cui
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jian-Juan
authors.initials: JJ
authors.lastname: Ke
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008026:Ligation / Q000009:adverse effects; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D013127:Spinal Nerves / Q000378:metabolism / Q000503:physiopathology*; D000077337:Vorinostat
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000077337:Vorinostat