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Characterization of a rat model of bortezomib-induced painful neuropathy.

Abstract：

BACKGROUND AND PURPOSE:Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterize a clinically relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery. EXPERIMENTAL APPROACH:Adult male Sprague-Dawley rats were injected i.p. with 0.1 and 0.2 mg·kg-1 bortezomib, or its vehicle, on days 0, 3, 7 and 10. Multiple behavioural approaches were utilized: mechanical hypersensitivity, cold allodynia, heat hypersensitivity, motor co-ordination, burrowing and voluntary wheel running. At maximal bortezomib-induced mechanical hypersensitivity, 200 mg·kg-1 ethosuximide/vehicle and 100 mg·kg-1 phenyl N-tert-butylnitrone (PBN)/vehicle were administered i.p. in separate experiments, and mechanical hypersensitivity assessed 1, 3 and 24 h later. KEY RESULTS:Bortezomib induced dose-related mechanical hypersensitivity for up to 80 days. Bortezomib induced short-term cold allodynia, but no significant change in heat hypersensitivity, motor co-ordination, voluntary wheel running and burrowing behaviour compared to vehicle-treated controls. Systemic PBN and ethosuximide significantly ameliorated bortezomib-induced mechanical hypersensitivity. CONCLUSIONS AND IMPLICATIONS:These data characterize a reproducible rat model of clinical-grade bortezomib-induced neuropathy demonstrating long-lasting pain behaviours to evoked stimuli. Inhibition by ethosuximide and PBN suggests involvement of calcium and/or ROS in bortezomib-induced painful neuropathy. These drugs could be used as preclinical positive controls to assess novel analgesics. As ethosuximide is widely used clinically, translation to the clinic to treat bortezomib-induced painful neuropathy may be possible.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Duggett NA,Flatters SJL

doi

10.1111/bph.14063

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

4812-4825

issue

eissn

0007-1188

issn

1476-5381

journal_volume

174

pub_type

杂志文章

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Characterization of a rat model of bortezomib-induced painful neuropathy.