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

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 Ca(2+/)Mg(2+) 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.

• Authors: Jennifer R Deuis, Yu Ling Lim, Silmara Rodrigues de Sousa, Richard J Lewis, Paul F Alewood, Peter J Cabot, Irina Vetter
• Journal: Neuro-oncology (Neuro Oncol) Vol. 16 Issue 10 Pg. 1324-32 (Oct 2014) ISSN: 1523-5866 [Electronic] England
• PMID: 24714523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Analgesics
• Antineoplastic Agents
• NAV1.6 Voltage-Gated Sodium Channel
• Organoplatinum Compounds
• Scn8a protein, mouse
• Oxaliplatin
• Cisplatin

Topics

• Analgesics (administration & dosage)
• Animals
• Antineoplastic Agents (toxicity)
• Cisplatin (toxicity)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hyperalgesia (chemically induced, drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• NAV1.6 Voltage-Gated Sodium Channel (metabolism)
• Organoplatinum Compounds (toxicity)
• Oxaliplatin
• Polyneuropathies (chemically induced, drug therapy)