Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice.
BACKGROUND
Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain.


RESULTS
In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR), we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG) neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG) were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons.


CONCLUSIONS
These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.
Ta
Lauren E
LE
Program in Molecular Neuroscience, Mayo Graduate School, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. ta.lauren@mayo.edu
Bieber
Allan J
AJ
Carlton
Susan M
SM
Loprinzi
Charles L
CL
Low
Philip A
PA
Windebank
Anthony J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D002945:Cisplatin