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


CONCLUSIONS
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.
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Jennifer R
JR
Deuis
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Yu Ling
YL
Lim
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Silmara
S
Rodrigues de Sousa
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Richard J
RJ
Lewis
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Paul F
PF
Alewood
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Peter J
PJ
Cabot
School of Pharmacy, The University of Queensland, Woolloongabba, Australia (J.R.D., Y.L.L., P.J.C., I.V.); Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.R.D., S.R., R.J.L., P.F.A., I.V.).
Irina
I
Vetter
D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D011115:Polyneuropathies / Q000139:chemically induced / Q000188:drug therapy*
D000700:Analgesics; D000970:Antineoplastic Agents; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009944:Organoplatinum Compounds; C491046:Scn8a protein, mouse; D000077150:Oxaliplatin; D002945:Cisplatin
Nav1.6; analgesia; chemotherapy-induced neuropathy; cisplatin; oxaliplatin