electrophysiological, behavioural and morphological characterization of oxaliplatin-induced painful peripheral neuropathy in mice

Oxaliplatin (OHP) is a platinum-based drug used as first-line chemotherapy for the treatment of metastatic colorectal cancer. It acts by inducing DNA crosslinks that result in apoptotic cell death of dividing cells. However 10-40% of cancer patients treated with a regimen that includes OHP are affected by a severe painful peripheral neuropathy (PN). Chronic OHP-induced PN is characterized by a persistent sensory dysfunction while transient paresthesias and dysesthesias, enhanced by exposure to cold, are the features of the acute PN. Rat models of OHP-induced PN have been successfully in describing their pathophysiology, but they are not enough to examine the drug-related neurotoxicity and neuropathic pain with the effects of antineoplastic activity since most cancer models are developed in mice. In this work we characterized the effects induced by chronic, bi-weekly intravenous administration of OHP at the four-week time point in balb-c mice. We measured caudal and digital nerve conduction velocities (NCV), we performed a pathological/morphometrical analysis of dorsal root ganglia (DRG) and sciatic nerve and we assessed changes in mechanical and thermal sensitivity through Von Fray and Heat/Cold Plate tests, respectively. Moreover, we performed electrophysiological recordings of the electrical activity of wide dynamic range neurons located in the lamina 5 of spinal dorsal horn in order to investigate relevant spinal cord structures involved in neuropathic pain. OHP treatment induced a significant impairment of the caudal and digital NCV and of the caudal nerve action potential amplitude. At the light and electron microscope analysis, the DRG of OHP-treated mice showed frequent multinucleolated neurons with eccentric nucleoli. Moreover, the morphometrical analysis of DRG revealed neuronal atrophy. In addition, OHP induced the development of significant mechanical allodynia and cold, but not heat, hyperalgesia, starting from the first week of treatment. Finally, the electrophysiological assessments performed in the spinal dorsal horn revealed that, despite the incapacity of the drug to cross the blood-brain barrier, OHP treatment induced a significant increase in the electrical activity of the wide dynamic range neurons in the spinal dorsal horn after both light and heavy mechanical stimulation.