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Characterisation of a rat model of bortezomib induced painful neuropathy

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)4812-4825
JournalBritish Journal of Pharmacology
Volume174
Issue number24
Early online date3 Oct 2017
DOIs
Accepted/In press26 Sep 2017
E-pub ahead of print3 Oct 2017
PublishedDec 2017

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Abstract

BACKGROUND: 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 characterise 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 intraperitoneally (i.p.) with 0.1, 0.2mg kg(-1) Bortezomib, or its vehicle, on days 0, 3, 7 and 10. Multiple behavioural approaches were utilised; mechanical hypersensitivity, cold allodynia, heat hypersensitivity, motor co-ordination, burrowing and voluntary wheel running. At maximal bortezomib-induced mechanical hypersensitivity, 200mg kg(-1) ethosuximide/vehicle and 100mg kg(-1) PBN (Phenyl N-tert-butylnitrone)/vehicle were administered i.p., in separate experiments, and mechanical hypersensitivity assessed 1, 3 and 24 hours 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 compared to vehicle-controls.

CONCLUSIONS & IMPLICATIONS: These data characterise 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.

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