Electrophysiological Characterization of Painful Peripheral Neuropathy Induced by Bortezomib in Rats

Bortezomib (BTZ) is an antineoplastic drug mainly used for the treatment of multiple myeloma and some types of solid tumors. Despite its effectiveness, BTZ clinical use is frequently limited by the onset of painful peripheral neuropathy, generally associated with alterations of A delta and C type primary afferent fibers. The neurotoxic mechanisms of BTZ remain poorly understood, although proteotoxic stress and mitochondrial impairment may contribute to the pathogenesis of the sensory distal neuropathy. To evaluate these aspects, spinal cord electrophysiological recordings and behavioral test alterations for neuropathic pain and immunohistochemistry studies of pain-related sensory biomarkers were performed in a Wistar rat model of BTZ-induced painful peripheral neuropathy. Then, three different analgesic drugs (CR4056, Gabapentin and Buprenorphine) were tested against BTZ-painful neuropathy. The animals were intravenously treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks, followed by 2 weeks of analgesic administrations. Bortezomib induced both mechanical allodynia and peripheral neuropathy in rats after 8 weeks of treatment. CR4056 was able to recover the painful condition without changing the nerve structural damage. Moreover, BTZ- induced changes both in the electrical activity of wide dynamic range neurons, and in the transient receptor potential vanilloid type 1 receptor (TRPV1) and neuropeptides calcitonin gene-related peptide (CGRP) immunolabeling expression in the spinal cord. In conclusion, the results of the study suggest that the alteration in the spinal cord electrophysiological recordings and CGRP/TRPV1 levels modulation are involved in the persistence pain symptoms in BTZ-induced peripheral neuropathy. Therefore, this model will enable us to test promising analgesic drugs designed to ameliorate or restore painful condition, and to compare it with standard compounds.