title: L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats.
abstract: BACKGROUND
  Oxaliplatin is an important drug used in the treatment of colorectal cancer. However, it frequently causes severe acute and chronic peripheral neuropathies. We recently reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats, and that oxalate derived from oxaliplatin is involved in the cold hyperalgesia. In the present study, we examined the effects of Ca²⁺ channel blockers on oxaliplatin-induced cold hyperalgesia in rats.
  
  
  METHODS
  Cold hyperalgesia was assessed by the acetone test. Oxaliplatin (4 mg/kg), sodium oxalate (1.3 mg/kg) or vehicle was injected i.p. on days 1 and 2. Ca²⁺ (diltiazem, nifedipine and ethosuximide) and Na⁺ (mexiletine) channel blockers were administered p.o. simultaneously with oxaliplatin or oxalate on days 1 and 2.
  
  
  RESULTS
  Oxaliplatin (4 mg/kg) induced cold hyperalgesia and increased in the transient receptor potential melastatin 8 (TRPM8) mRNA levels in the dorsal root ganglia (DRG). Furthermore, oxalate (1.3 mg/kg) significantly induced the increase in TRPM8 protein in the DRG. Treatment with oxaliplatin and oxalate (500 μM for each) also increased the TRPM8 mRNA levels and induced Ca²⁺ influx and nuclear factor of activated T-cell (NFAT) nuclear translocation in cultured DRG cells. These changes induced by oxalate were inhibited by nifedipine, diltiazem and mexiletine. Interestingly, co-administration with nifedipine, diltiazem or mexiletine prevented the oxaliplatin-induced cold hyperalgesia and increase in the TRPM8 mRNA levels in the DRG.
  
  
  CONCLUSIONS
  These data suggest that the L type Ca²⁺ channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca²⁺ channel blockers have prophylactic potential for acute neuropathy.
authors.affiliation: Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kawashiri
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kurobe
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ushio
authors.forename: Takahisa
authors.initials: T
authors.lastname: Yano
authors.forename: Ryozo
authors.initials: R
authors.lastname: Oishi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003080:Cold Temperature; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism; D009944:Organoplatinum Compounds; D010070:Oxalates / Q000494:pharmacology; D000077150:Oxaliplatin; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D050778:NFATC Transcription Factors; D009944:Organoplatinum Compounds; D010070:Oxalates; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D000077150:Oxaliplatin; D002118:Calcium