Pain Scientific Publications

Latest publication 02/05/2025

Characterization of a rat model of bortezomib-induced painful neuropathy

Background and Purpose Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However,...

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    [title] => Characterization of a rat model of bortezomib-induced painful neuropathy
    [paragraph] => Characterization of a rat model of bortezomib-induced painful neuropathy
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Authors
Natalie A Duggett, Sarah J L Flatters

Lab
Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Journal
British Journal of Pharmacology
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.
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