Activity, Motor Control & Coordination
Pain - Thermal Allodynia / Hyperalgesia
Pain - Spontaneous Pain - Postural Deficit
Pain - Mechanical Allodynia / Hyperalgesia
Anxiety & Depression Disorder
Learning/Memory - Attention - Addiction
Physiology & Respiratory Research
Metabolism - Food & Drink Intake
Pain
Central Nervous System (CNS)
Neurodegeneration
Sensory system
Motor control
Mood Disorders
Other disorders
Muscular system
Joints
Metabolism
Cross-disciplinary subjectsAuthors
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.
