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Molecular Pain
Published in: Molecular Pain 1/2012

Open Access 01-12-2012 | Research

L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats

Authors: Takehiro Kawashiri, Nobuaki Egashira, Kentaro Kurobe, Kuniaki Tsutsumi, Yuji Yamashita, Soichiro Ushio, Takahisa Yano, Ryozo Oishi

Published in: Molecular Pain | Issue 1/2012

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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.
Appendix
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Metadata
Title
L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats
Authors
Takehiro Kawashiri
Nobuaki Egashira
Kentaro Kurobe
Kuniaki Tsutsumi
Yuji Yamashita
Soichiro Ushio
Takahisa Yano
Ryozo Oishi
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2012
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-8-7

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