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.
Characterisation of a rat model of bortezomib induced painful neuropathy
01.12.2017
Duggett , N A & Flatters , S J L 2017 , ' Characterisation of a rat model of bortezomib induced painful neuropathy ' , British Journal of Pharmacology , vol. 174 , no. 24 , pp. 4812-4825 . https://doi.org/10.1111/bph.14063
Aufsatz (Zeitschrift)
Elektronische Ressource
Englisch
DDC: | 629 |
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