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Bortezomib‐induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats
Author(s) -
Meregalli Cristina,
Canta Annalisa,
Carozzi Valentina A.,
Chiorazzi Alessia,
Oggioni Norberto,
Gilardini Alessandra,
Ceresa Cecilia,
Avezza Federica,
Crippa Luca,
Marmiroli Paola,
Cavaletti Guido
Publication year - 2010
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1016/j.ejpain.2009.07.001
Subject(s) - bortezomib , medicine , neuropathic pain , pathological , peripheral neuropathy , allodynia , gabapentin , anesthesia , proteasome inhibitor , neurotoxicity , nociception , multiple myeloma , hyperalgesia , toxicity , pathology , endocrinology , receptor , alternative medicine , diabetes mellitus
Bortezomib is a proteasome inhibitor showing strong antitumor activity against many tumors, primarily multiple myeloma. Bortezomib‐induced neuropathic pain is the main side effect and the dose‐limiting factor of the drug in clinical practice. In order to obtain a pre‐clinical model to reproduce the characteristic pain symptoms in bortezomib‐treated patients, we developed an animal model of bortezomib‐induced nociceptive sensory neuropathy. In this study, bortezomib (0.15 or 0.20mg/kg) was administered to Wistar rats three times/week for 8 weeks, followed by a 4 week follow‐up period. At the end of the treatment period a significant decrease in weight gain was observed in the treated groups vs. controls, and hematological and histopathological parameters were evaluated. After the treatment period, both doses of bortezomib induced a severe reduction in nerve conduction velocity and demonstrated a dose‐cumulative effect of the drug. The sensory behavioral assessment showed the onset of mechanical allodynia, while no effect on thermal perception was observed. Sciatic nerves and dorsal root ganglia (DRG) were collected at the end of the 8‐week treatment and at the end of the follow‐up period. The pathological examination revealed a dose‐dependent axonopathy of the unmyelinated fibers in nerves of treated animals. No pathological alteration in most of DRG satellite cells and neurons was observed. Therefore, this animal model may be useful for studying the neurotoxicity and pain onset mechanisms related to bortezomib treatment.