title: Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in rats.
abstract: BACKGROUND
  Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats.
  
  
  RESULTS
  An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.
  
  
  CONCLUSIONS
  These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.
authors.affiliation: Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Shirahama
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ushio
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Shota
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sada
authors.forename: Ken
authors.initials: K
authors.lastname: Masuguchi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kawashiri
authors.forename: Ryozo
authors.initials: R
authors.lastname: Oishi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001596:Benzylamines / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010636:Phenols / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use; D014268:Trifluoperazine / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D014150:Antipsychotic Agents; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010636:Phenols; D010880:Piperidines; D013449:Sulfonamides; D014268:Trifluoperazine; C109643:Ro 25-6981; C072105:KN 93; D000096926:Benzenesulfonamides