Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in rats.
Mol Pain
; 8: 26, 2012 Apr 17.
Article
em En
| MEDLINE
| ID: mdl-22510452
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Organoplatínicos
/
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
/
Hiperalgesia
Limite:
Animals
Idioma:
En
Revista:
Mol Pain
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
/
PSICOFISIOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Japão