title: Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and etanercept.
abstract: BACKGROUND
  Painful neuropathy is a dose-limiting side effect in cancer chemotherapy. To characterize this phenomenon, we examined pain behavior and analgesic actions in a mouse model of cisplatin polyneuropathy.
  
  
  METHODS
  Male C57BL/6 mice received intraperitoneal cisplatin or saline (2.3 mg/kg/d) every other day 6 times over 2 weeks for a total dose of 13.8 mg/kg. Thermal escape latencies, mechanical allodynia using von Frey hairs, and observation of behavior/morbidity and body weights were assessed. After onset of allodynia, we examined the actions of intraperitoneal gabapentin (100 mg/kg), etanercept (20 and 40 mg/kg), ketorolac (15 mg/kg), and morphine (1, 3, and 10 mg/kg). Additionally, using the conditioned place preference (CPP) paradigm, we examined the effects of gabapentin and ketorolac on the presumed pain state initiated by cisplatin. Additionally, we examined the spinal cord and dorsal root ganglia (DRG) of cisplatin-treated mice.
  
  
  RESULTS
  Cisplatin, but not saline treatment, produced persistent hindpaw tactile allodynia, which persisted 46 days with no effect on thermal escape. Gabapentin and morphine, but neither etanercept nor ketorolac, produced a complete but transient (2-hour) reversal of the allodynia. Etanercept (40 mg/kg) pretreatment resulted in a delay in onset of mechanical allodynia. Using CPP, gabapentin, but not ketorolac, in cisplatin animals resulted in a significant preference for the drug-associated treatment compartment. There was no place preference in non-cisplatin-treated (nonallodynic) mice after gabapentin injection. Immunohistochemistry in cisplatin-treated mice showed no change in glial fibrillary acidic protein (astrocyte) or Iba1 (ionized calcium binding adaptor molecule 1) (microglia) activation states, but a significant increase in activated transcription factor 3 was observed in the DRG.
  
  
  CONCLUSIONS
  Cisplatintreated mice display allodynia and an activation of DRG activated transcription factor 3, which is paralleled by its effects on behavior in the CPP system, wherein gabapentin, but not ketorolac, in the presence of the cisplatin polyneuropathy, is positively rewarding, confirming that this neuropathy is an aversive (painful) state that is ameliorated by gabapentin.
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Hue Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stokes
authors.forename: Elaine
authors.initials: E
authors.lastname: Pirie
authors.forename: James
authors.initials: J
authors.lastname: Skahen
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shtaerman
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents; D001522:Behavior, Animal / Q000187:drug effects; D002945:Cisplatin; D003216:Conditioning, Operant / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D000068800:Etanercept; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D007150:Immunohistochemistry; D020911:Ketorolac Tromethamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D058127:Transcription Factor 3 / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D003509:Cyclohexanecarboxylic Acids; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D058127:Transcription Factor 3; D020911:Ketorolac Tromethamine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine; D000068800:Etanercept; D002945:Cisplatin