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L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats.
Mol Pain. 2012 Jan 31; 8:7.MP

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+Show Affiliations

Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22292988

Citation

Kawashiri, Takehiro, et al. "L Type Ca²+ Channel Blockers Prevent Oxaliplatin-induced Cold Hyperalgesia and TRPM8 Overexpression in Rats." Molecular Pain, vol. 8, 2012, p. 7.
Kawashiri T, Egashira N, Kurobe K, et al. L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. Mol Pain. 2012;8:7.
Kawashiri, T., Egashira, N., Kurobe, K., Tsutsumi, K., Yamashita, Y., Ushio, S., Yano, T., & Oishi, R. (2012). L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. Molecular Pain, 8, 7. https://doi.org/10.1186/1744-8069-8-7
Kawashiri T, et al. L Type Ca²+ Channel Blockers Prevent Oxaliplatin-induced Cold Hyperalgesia and TRPM8 Overexpression in Rats. Mol Pain. 2012 Jan 31;8:7. PubMed PMID: 22292988.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. AU - Kawashiri,Takehiro, AU - Egashira,Nobuaki, AU - Kurobe,Kentaro, AU - Tsutsumi,Kuniaki, AU - Yamashita,Yuji, AU - Ushio,Soichiro, AU - Yano,Takahisa, AU - Oishi,Ryozo, Y1 - 2012/01/31/ PY - 2011/07/12/received PY - 2012/01/31/accepted PY - 2012/2/2/entrez PY - 2012/2/2/pubmed PY - 2012/6/1/medline SP - 7 EP - 7 JF - Molecular pain JO - Mol Pain VL - 8 N2 - 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/22292988/L_type_Ca²+_channel_blockers_prevent_oxaliplatin_induced_cold_hyperalgesia_and_TRPM8_overexpression_in_rats_ L2 - https://journals.sagepub.com/doi/10.1186/1744-8069-8-7?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -