title: Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice.
abstract: BACKGROUND
  Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1) in oxaliplatin-induced acute hypersensitivity was investigated in mice.
  
  
  RESULTS
  A single intraperitoneal administration of oxaliplatin (1-10 mg/kg) induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg), also induced acute cold hypersensitivity, while another platinum-based chemotherapeutic agent, cisplatin (5 mg/kg), or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg) failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg) and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl-isothiocyanate (AITC; TRPA1 agonist) were significantly enhanced in mice treated for 2 h with oxaliplatin (1-10 mg/kg) in a dose-dependent manner, while capsaicin (TRPV1 agonist)-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist)-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG) neurons with oxaliplatin (30-300 μM) for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons.
  
  
  CONCLUSIONS
  Taken together, these results suggest that a brief treatment with oxaliplatin or its metabolite oxalate is sufficient to enhance the responsiveness of TRPA1 but not that of TRPM8 and TRPV1 expressed by DRG neurons, which may contribute to the characteristic acute peripheral neuropathy induced by oxaliplatin.
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Meng
authors: M
authors: Zhao
authors: Kouichi
authors: K
authors: Isami
authors: Saki
authors: S
authors: Nakamura
authors: Hisashi
authors: H
authors: Shirakawa
authors: Takayuki
authors: T
authors: Nakagawa
authors: Shuji
authors: S
authors: Kaneko
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism; D002211:Capsaicin; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D056587:Cryopyrin-Associated Periodic Syndromes / Q000139:chemically induced* / Q000473:pathology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology; D017879:Isothiocyanates; D008297:Male; D008610:Menthol; D051379:Mice; D008810:Mice, Inbred C57BL; D059225:Nociception / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D017879:Isothiocyanates; D009944:Organoplatinum Compounds; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D008610:Menthol; C004471:allyl isothiocyanate; D017239:Paclitaxel; D002945:Cisplatin; D002211:Capsaicin