Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin

Deuis, Jennifer R., Lim, Yu Ling, Rodrigues de Sousa, Silmara, Lewis, Richard J., Alewood, Paul F., Cabot, Peter J. and Vetter, Irina (2014) Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin. Neuro-Oncology, 16 10: 1324-1332. doi:10.1093/neuonc/nou048


Author Deuis, Jennifer R.
Lim, Yu Ling
Rodrigues de Sousa, Silmara
Lewis, Richard J.
Alewood, Paul F.
Cabot, Peter J.
Vetter, Irina
Title Analgesic effects of clinically used compounds in novel mouse models of polyneuropathy induced by oxaliplatin and cisplatin
Journal name Neuro-Oncology   Check publisher's open access policy
ISSN 1523-5866
1522-8517
Publication date 2014-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/neuonc/nou048
Volume 16
Issue 10
Start page 1324
End page 1332
Total pages 9
Place of publication Cary, NC, United States
Publisher Oxford University Press
Language eng
Formatted abstract
Background Peripheral neuropathy is the major dose-limiting side effect of cisplatin and oxaliplatin, and there are currently no effective treatments available. The aim of this study was to assess the pharmacological mechanisms underlying chemotherapy-induced neuropathy in novel animal models based on intraplantar administration of cisplatin and oxaliplatin and to systematically evaluate the analgesic efficacy of a range of therapeutics.

Methods Neuropathy was induced by a single intraplantar injection of cisplatin or oxaliplatin in C57BL/6J mice and assessed by quantification of mechanical and thermal allodynia. The pharmacological basis of cisplatin-induced neuropathy was characterized using a range of selective pharmacological inhibitors. The analgesic effects of phenytoin, amitriptyline, oxcarbazepine, mexiletine, topiramate, retigabine, gabapentin, fentanyl, and Ca2+/Mg2+ were assessed 24 hours after induction of neuropathy.

Results Intraplantar administration of cisplatin led to the development of mechanical allodynia, mediated through Nav1.6-expressing sensory neurons. Unlike intraplantar injection of oxaliplatin, cold allodynia was not observed with cisplatin, consistent with clinical observations. Surprisingly, only fentanyl was effective at alleviating cisplatin-induced mechanical allodynia despite a lack of efficacy in oxaliplatin-induced cold allodynia. Conversely, lamotrigine, phenytoin, retigabine, and gabapentin were effective at reversing oxaliplatin-induced cold allodynia but had no effect on cisplatin-induced mechanical allodynia. Oxcarbazepine, amitriptyline, mexiletine, and topiramate lacked efficacy in both models of acute chemotherapy-induced neuropathy.

Conclusion This study established a novel animal model of cisplatin-induced mechanical allodynia consistent with the A-fiber neuropathy seen clinically. Systematic assessment of a range of therapeutics identified several candidates that warrant further clinical investigation.
Keyword Analgesia
Chemotherapy-induced neuropathy
Cisplatin
NA(V)1.6
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 8 April 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Pharmacy Publications
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 22 May 2014, 21:09:27 EST by Susan Allen on behalf of Institute for Molecular Bioscience