L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats.
Mol Pain
; 8: 7, 2012 Jan 31.
Article
en En
| MEDLINE
| ID: mdl-22292988
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 Ca²âº 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. Ca²âº (diltiazem, nifedipine and ethosuximide) and Na⺠(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 Ca²âº 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 Ca²âº channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca²âº channel blockers have prophylactic potential for acute neuropathy.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Bloqueadores de los Canales de Calcio
/
Frío
/
Canales de Calcio Tipo L
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Canales Catiónicos TRPM
/
Hiperalgesia
Límite:
Animals
Idioma:
En
Revista:
Mol Pain
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
/
PSICOFISIOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón