Molecular Characterization of Oxaliplatin-Induced Peripheral Neurotoxicity: The Complex Spectrum of Painful Manifestations

Background and aims: Oxaliplatin (OHP) induced peripheral neurotoxicity (OIPN) is a complex spectrum comprising an acute and a chronic form. Acute OIPN leads to unpleasant transient sensations in the 24-72 h after chemotherapy, due to a temporary dysfunction in ion channels (i.e., axonal hyperexcitability in the absence of anatomical damage). Whereas chronic OIPN is characterized by painful manifestations. Literature data showed that a more pronounced acute OIPN could be an early predictor of chronic OIPN; thus, acute OIPN is becoming a possible target to prevent chronic OIPN. We went back to the bench side to characterize the complexity of painful phenomena experienced by OHP-treated patients. Methods: Female OHP-treated (3 mg/Kg, 2qwx4ws, iv) and control rats (n = 10/group) were studied. Acute OIPN was detected via nerve excitability testing (NET), whereas chronic OIPN was assessed via behavioral tests, nerve conduction studies (NCS), and neuropathology (including immunohistochemistry on lumbar spinal cord specimens) both at the end of the full chemotherapy treatment (4 weeks) and at 6 weeks of follow-up. NET was also performed 1 week after treatment completion. Results: NET alterations related to acute OIPN were resolved within a week after chemotherapy. Whereas, chronic OIPN encountered only partial recovery over time, with prominent small fiber damage. Immunolabeling of the spinal cord at the end of treatment and after the follow-up period was consistent with persistent neuropathic pain. Interpretation: Our data supports the statement that unpleasant manifestations due to acute and chronic OIPN mirror different underlying phenomena and assessment as two separate entities should be considered in both clinical and preclinical studies.