title: Spinal CPEB-mtROS-CBP signaling pathway contributes to perineural HIV gp120 with ddC-related neuropathic pain in rats.
abstract: Human immunodeficiency virus (HIV) patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), have been known to develop neuropathic pain. While there has been a major shift away from some neurotoxic NRTIs in current antiretroviral therapy, a large number of HIV patients alive today have previously received them, and many have developed painful peripheral neuropathy. The exact mechanisms by which HIV with NRTIs contribute to the development of neuropathic pain are not known. Previous studies suggest that cytoplasmic polyadenylation element-binding protein (CPEB), reactive oxygen species (ROS), and cAMP-response element-binding protein (CREB)-binding protein (CBP), are involved in the neuroimmunological diseases including inflammatory/neuropathic pain. In this study, we investigated the role of CPEB, mitochondrial ROS (mtROS), or CBP in neuropathic pain induced by HIV envelope protein gp120 combined with antiretroviral drug. The application of recombinant gp120 into the sciatic nerve plus systemic ddC (one of NRTIs) induced mechanical allodynia. Knockdown of CPEB or CBP using intrathecal antisense oligodeoxynucleotide (AS-ODN) reduced mechanical allodynia. Intrathecal mitochondrial superoxide scavenger mito-tempol (Mito-T) increased mechanical withdrawal threshold. Knockdown of CPEB using intrathecal AS-ODN, reduced the up-regulated mitochondrial superoxide in the spinal dorsal horn in rats with gp120 combined with ddC. Intrathecal Mito-T lowered the increased expression of CBP in the spinal dorsal horn. Immunostaining studies showed that neuronal CPEB positive cells were co-localized with MitoSox positive profiles, and that MitoSox positive profiles were co-localized with neuronal CBP. Our studies suggest that neuronal CPEB-mtROS-CBP pathway in the spinal dorsal horn, plays an important role in the gp120/ddC-induced neuropathic pain in rats.
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Department of Anesthesiology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Hyun
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Shue
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Wan
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Department of Anesthesiology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Lubarsky
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States. Electronic address: shao@med.miami.edu.
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Hao
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D059408:Pain Management; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D016047:Zalcitabine / Q000633:toxicity; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; C490386:CPEB1 protein, human; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C408142:Pag1 protein, rat; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; D016047:Zalcitabine; D013385:Succinate Dehydrogenase; D010751:Phosphopyruvate Hydratase
keywords: CBP; CPEB; HIV; Neuropathic pain; ROS