POTENTIAL FOR ENDOCANNABINOID SYSTEM IMPLICATION IN NEUROPATHIC PAIN AND INFLAMMATION IN BORTEZOMIB-INDUCED PERIPHERAL NEUROTOXICITY

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a significant complication in the successful treatment of many cancers. For several antineoplastic agents neurotoxicity is common, severe, usually doselimiting, and clinically reflected in an axonal peripheral neuropathy with glove-and-stocking distribution of sensory loss, often associated with neuropathic pain. These symptoms may be disabling, adversely affecting activities of daily living and thereby quality of life of cancer patients. In particular, we have focused on bortezomib, a first-in-class proteasome inhibitor used for the treatment of multiple myeloma, which is associated with a relatively high incidence of CIPN. The pathogenesis of CIPN has not been completely understood, and there are no effective strategies to prevent this side effect, with limited evidence of effective drugs for treating established neurotoxicity. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising. To investigate this hypothesis, we performed electrophysiological, behavioral and pathological analyses in a rat model of painful CIPN induced by treatment with bortezomib. The animals were intravenously injected with bortezomib 0.20 mg/kg, 3 times a week for 8 weeks. Moreover, localization of CB1R/CB2R-like immunoreactivity and protein quantification for CB1R/CB2R were performed in dorsal root ganglion (DRG) and in the spinal cord. In addition, CD68 positive macrophages in the peripheral nerve as well as resident macrophages (Iba-1) positive cells or microglia were also evaluated in the DRG and spinal cord dorsal horn, respectively. Bortezomib induced significant alterations in rat electrophysiological endpoints and behavioral studies of pain associated with a significant reduction in IENF density if compared to control rats. Moreover, huge M1 proinflammatory infiltrating cells in caudal nerves and increased Iba-1 positive cells in DRG and microglia in the spinal cord dorsal horn of rats after 8 weeks of treatment were also observed. In addition, bortezomib induced an increase in the number of CB1R- and CB2Rpositive DRG neurons, as well as a significant increase in CB1R and CB2R protein expression in DRG. The densitometry analysis on BTZtreated dorsal horn showed a significant increase in CB1R immunoreactivity, while slight changes regarding CB1R expression were observed in the spinal cord. In conclusion, the results suggest that the alteration of the endocannabinoid levels in peripheral and central nervous tissues could be involved in the development and progression of CIPN. Therefore, improved understanding of the pathophysiology of bortezomibinduced neurotoxicity will inevitably assist in the development of effective pharmacological intervention on the cannabinoid system as potential therapy for CIPN.