title: Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats.
abstract: BACKGROUND
  In the human immunodeficiency virus (HIV)-associated sensory neuropathy, neuropathic pain associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/acquired immunodeficiency syndrome is clinically common. While evidence demonstrates that neuropathic pain is influenced by neuroinflammatory events that include the proinflammatory molecules, tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1-α (SDF1-α), and C-X-C chemokine receptor type 4 (CXCR4), the detailed mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In this study, we investigated the role of these proinflammatory molecules in the dorsal root ganglion (DRG) and the spinal dorsal horn in NRTIs-mediated neuropathic pain state.
  
  
  METHODS
  Neuropathic pain was induced by intraperitoneal administration of 2',3'-dideoxycytidine (ddC, one of the NRTIs). Mechanical threshold was tested using von Frey filament fibers. Nonreplicating herpes simplex virus (HSV) vectors expressing p55 TNF soluble receptor (p55TNFSR) were inoculated into hindpaw of rats. The expression of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG was examined using Western blots. Intrathecal CXCR4 antagonist was administered.
  
  
  RESULTS
  The present study demonstrated that (1) systemic ddC induced upregulation of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG; (2) p55TNFSR mediated by a nonreplicating HSV vector reversed mechanical allodynia induced by systemic ddC; (3) intrathecal administration of the CXCR4 antagonist AMD3100 increased mechanical threshold; and (4) HSV vector expressing p55TNFSR reversed upregulation of TNF-α, SDF1-α, and CXCR4 induced by ddC in the lumbar spinal dorsal horn and the DRG.
  
  
  CONCLUSIONS
  Our studies demonstrate that TNF-α through the SDF1/CXCR4 system is involved in the NRTIs-related neuropathic pain state and that blocking the signaling of these proinflammatory molecules is able to reduce NRTIs-related neuropathic pain. These results provide a novel mechanism-based approach (gene therapy) to treating HIV-associated neuropathic pain.
authors.affiliation: From the *Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida; †Department of Anesthesiology, State Key Laboratory of Oncology on Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China; ‡Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan; §Hussman Institute of Human Genomics, University of Miami Miller School of Medicine; and ‖Veterans Affairs Medical Center, Miami, Florida.
authors.forename: Wan
authors.initials: W
authors.lastname: Huang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zheng
authors.forename: Handong
authors.initials: H
authors.lastname: Ouyang
authors.forename: Hyun
authors.initials: H
authors.lastname: Yi
authors.forename: Shue
authors.initials: S
authors.lastname: Liu
authors.forename: Weian
authors.initials: W
authors.lastname: Zeng
authors.forename: Roy C
authors.initials: RC
authors.lastname: Levitt
authors.forename: Keith A
authors.initials: KA
authors.lastname: Candiotti
authors.forename: David A
authors.initials: DA
authors.lastname: Lubarsky
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Hao
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D018139:Simplexvirus / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D016047:Zalcitabine / Q000633:toxicity
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D018124:Receptors, Tumor Necrosis Factor; D018894:Reverse Transcriptase Inhibitors; D016047:Zalcitabine