title: Triptolide prevents and attenuates neuropathic pain via inhibiting central immune response.
abstract: BACKGROUND
  Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells.
  
  
  OBJECTIVE
  In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide.
  
  
  METHODS
  A randomized, double blind, controlled animal trial.
  
  
  METHODS
  Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle during the period of days 11-20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study.
  
  
  RESULTS
  A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide.
  
  
  CONCLUSIONS
  The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia.
  
  
  CONCLUSIONS
  Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn.
authors.affiliation: Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, the Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Mei
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Li
authors.forename: Sheng-Xi
authors.initials: SX
authors.lastname: Wu
authors.forename: Li-Xian
authors.initials: LX
authors.lastname: Xu
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage*; D004852:Epoxy Compounds / Q000008:administration & dosage; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010616:Phenanthrenes / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000700:Analgesics; D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide