Electrophysiological and behavioral characterization of bortezomib-induced painful peripheral neuropathy in mice.

Bortezomib (BZ) is a potent and selective first-in-class proteasome inhibitor that is mainly used for the treatment of relapsed, refractory multiple myeloma. Peripheral neuropathy (PN) is a significant side effect of BZ-based chemotherapy and since it is one of the major reasons for a dose reduction and discontinuation of life-saving therapy, its mechanisms remain poorly understood. Metabolic changes resulting from the drug accumulation in the dorsal root ganglia (DRG) and mitochondrial disregulations may contribute to the pathogenesis of the painful, axonal, sensory distal neuropathy. Moreover BZ-induced pain is associated with deficits of all 3 major fibre types (Aβ, A , and C). We have characterized the pain sensations produced by 4 weeks of intravenous administration of BZ in balb-c mice assessing: - changes in mechanical/thermal thresholds through behavioral tests; - changes in the electrical activity of wide dynamic range neurons of the spinal dorsal horn of the spinal cord by electrophysiological recordings. BZ induced the development of significant mechanical allodynia starting from the first week of treatment to the end of the experiment. Moreover, the electrophysiological assessments performed in the spinal dorsal horn revealed that, despite the incapacity of the drug to cross the blood-brain barrier, it resulted in an increase in the activity of the wide dynamic range neurons, particularly after light stimulations of the hind paw. Our results demonstrate that the chronic treatment with BZ produces a painful neuropathy in a mouse model. Therefore, this model will enable us to conduct further mechanistic studies of BZ-related antineoplastic activity, peripheral neurotoxicity and pain and can be used as a reference in the preclinical discovery of new neuroprotective as well as of analgesic compounds. This work was partially funded by “AISAL, Associazione per le Scienze degli Animali da Laboratorio”.