title: Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice.
abstract: OBJECTIVE
  Cisplatin-treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g., tactile allodynia. The allodynia is associated with an up-regulation of activation transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLRs). Accordingly, we sought to examine the role of the TLR signaling cascade on allodynia, weight, and changes in DRG ATF3 in cisplatin-treated mice.
  
  
  METHODS
  Cisplatin (2.3 mg/kg/day × 6 injections every other day) or vehicle was administered to male wild-type (WT) C57BL/6, Tlr3 (-/-), Tlr4 (-/-), Myd88 (-/-), Trif (lps2) and Myd88/Trif (lps2) mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining.
  
  
  RESULTS
  (1) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. (2) The Myd88/Trif (lps2) mice did not show allodynia. (3) In Tlr3 (-/-), Tlr4 (-/-), and Myd88 (-/-) mice, withdrawal thresholds were elevated toward normal versus WT cisplatin-treated mice, but remained decreased as compared to vehicle mice. (4) In Trif (lps2) mice, cisplatin allodynia showed a delayed onset, but persisted. (5) In Tlr3 (-/-), Tlr4 (-/-), Myd88 (-/-), and Myd88/Trif (lps2) mice, the increase in DRG ATF3 was abolished. (6) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice.
  
  
  CONCLUSIONS
  Cisplatin evoked a persistent allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin polyneuropathy.
authors.affiliation: Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hue Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stokes
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D051700:Activating Transcription Factor 3 / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D051700:Activating Transcription Factor 3; D033942:Adaptor Proteins, Vesicular Transport; D000970:Antineoplastic Agents; D002945:Cisplatin; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C103002:Atf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse