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Bortezomib (BTZ), a selective proteasome inhibitor, is an antitumor drug used to treat multiple myeloma. As a side effect, BTZ determines a painful peripheral neuropathy (PPN), often refractory to management. Chronic BTZ administration in female Wistar rats induced a PPN in which the development of mechanical allodynia is associated to an increase in the expression of TRPV1 and CGRP in the dorsal root ganglia (DRG) and spinal cord dorsal horn. In this study we examine the possible role of two standard analgesics, Gabapentin (Gaba) and buprenorfin (Bupre), in modulating the expression of TRPV1 and CGRP in the DRG and spinal cord of rats chronically treated with BTZ. To this aim, female Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v.). Then Gaba (100 mg/kg, daily, p.o.) and Bupre (28,8 µg/kg, daily, s.c.) were orally administered in a curative schedule for 2 weeks. The expression of TRPV1 and CGRP, a neuropeptide involved in nociceptive neurotransmission, was examined in L4-L5 DRG and spinal cord segments by means of western blot (WB) and immunohistochemistry. WB analysis did not show any statistically significant change of protein levels in DRG and spinal cord. Instead, chronic BTZ treatment followed by a 2 weeks follow-up period affected TRPV1 expression by inducing an increase in the proportion of TRPV1-like immunoreactive (LI) DRG neurons, whereas did not affect the percentage of CGRP-LI neurons. Labeled perikarya were mostly of small- and medium-size. No BTZ-induced changes in immunolabeling were appreciable in the dorsal horn of the spinal cord. Treatment with Gaba and Bupre reduced levels of TRPV1 protein in spinal cord homogenates, whereas had no effect on DRG protein levels. None of the analgesics appeared to reverse in a statistically significant way the BTZ-induced increase of labelled DRG neurons nor induced any change in the detectability of positive innervation in the spinal cord dorsal horn.

Bortezomib (BTZ), a selective proteasome inhibitor, is a potent antineoplastic drug to treat multiple myeloma. In clinical practice, the most significant side effect of its administration, is a peripheral painful sensory neuropathy (PN), characterized by numbness and tingling in a distal stocking-glove distribution as well as distal paresthesia and generally associated with impairment of Adelta and C type primary afferent fibers. At the moment the therapies for PN are not really effective and almost only symptomatic. To evaluate if BTZ-induced sensory deficits are associated to loss of epidermal nerve fibers as is observed in other PN conditions, here we examine the effect of a well-established chronic BTZ-treatment schedule on the number of intraepidermal nerve fibers (IENF) in a rat model of BTZ-induced PN and compared the outcome of chronic BTZ-treatment followed by two-weeks of follow up with that of animals that received a 2-weeks treatment period with two analgesic drugs commonly used in clinical practice such as Gabapentin (Gaba) and buprenorphine (Bupre). To these aims, female Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v.). Then analgesic were orally administered according to the following curative schedule: Gaba (100 mg/kg, daily, p.o.), Bupre (28,8 μg/kg, daily, s.c.). At the end of treatments, the hindlimb footpad skin was examined by immunohistochemistry for the pan-neuronal marker PGP9.5 and the neuropeptide calcitonin gene-related peptide (CGRP), a neuropeptide involved in pain perception and neurotransmission. Labelled nerve fibers were distributed in the reticular and papillary dermis and within the epidermal lining. Quantitative evaluation of IENF showed that, according to the painful symptoms induced by BTZ, the mean linear density of CGRP-labelled IENF normalized by that of the PGP9.5-labelled ones shows a statistically significant decrease in BTZ-treated rats. None of the analgesics used in this study appeared to reverse the BTZ-induced loss of IENF. Results obtained suggest that the CGRP-positive innervation is likely involved in the persistence of BTZ-induced pain and that detectability of CGRP-positive IENF appears not to be related to the effectiveness of the selected analgesics.

Bortezomib (BTZ) is a proteasome inhibitor used as first-line therapy for multiple myeloma. However, its administration induces the development of severe painful peripheral neuropathy (PPN). This painful condition is an important medical need since the available treatments are actually ineffective. We recently described a mice model of PPN that shares most of the conditions found in patients treated chronically with BTZ (Carozzi et al., 2013). In fact, BTZ determines dysfunction of all fiber types in sensory nerves and, at least in mice, alters the electrical activity of the spinal dorsal horn neurons. This alteration of the basal electrophysiological activity induces also relevant changes in the central nociceptive transmission. In this work we characterize the neuroprotective effects of an imidazoline receptor 2 ligand (CR4056) able to allosterically inhibit the activity of monoamine oxidase-A, a key enzyme in the regulation of neuropathic pain. Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v). Then CR4056 was orally administered in a curative schedule at 6 mg/kg, once a day, for 2 weeks. Gabapentin (100 mg/kg, daily, p.o.) and buprenorphine (28,8µg/kg, daily, s.c.) were used as internal analgesic standards. At the end of both BTZ and analgesic treatments, we measured the caudal and sciatic nerve conduction velocity (NCV), the morphological/morphometrical alterations in the caudal nerve and the neuropathic pain development. BTZ treatment induced a significant impairment of sensory, but not motor NCV, slight hyperalgesia, significant mechanical allodynia and clearing of myelinated fibers in the caudal nerves. After two weeks of follow up animals did not spontaneously recover functional, morphological and behavioral abnormalities while the 2 weeks-treatment with CR4056 (but not with gabapentine and buprenorphine) significantly resolved BTZ-induced mechanical allodynia. Results obtained show that CR4056 produces a marked analgesic effects against BTZ-induced neuropathic pain without signs of tolerance. Carozzi VA, Renn CL, Bardini M. et al. PLoS One. 2013; 8(9):e72995.

To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established “chronic” schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.