Abstract 4384: Characterization of the painful peripheral neuropathy induced by oxaliplatin-based chemotherapy in mice
Authors: Carozzi Valentina Alda , Renn Cynthia , Rhee Peter , Gallop Danisha , Barbara Sala , Cristina Meregalli , Cavaletti Guido , Dorsey Susan 
Published: June 2012

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. A major clinical issue in the use of this drug is severe painful peripheral neuropathy (PN) that affects 10-40% of cancer patients treated with a regimen that includes OHP. Acute OHP-induced PN is characterized by transient paresthesias and dysesthesias enhanced by exposure to cold, while persistent sensory dysfunction is the hallmark of chronic PN. Rat models of OHP-induced PN have been used to describe pathophysiological features, but these models are not sufficient to examine the contribution of drug neurotoxicity and the neuropathic pain of OHP with the effects of antineoplastic activity since most cancer models are developed in mice.

We have characterized the effects induced by chronic, bi-weekly intravenous administration of OHP at the four-week timepoint in balb-c mice. We examined sciatic and digital nerve conduction velocities (NCV), the pathological/morphometrical analysis of dorsal root ganglia (DRG) and assessed changes in mechanical/thermal thresholds. Moreover, in order to investigate relevant spinal cord structures involved in neuropathic pain, we conducted electrophysiological recordings of wide dynamic range neurons in the spinal dorsal horn to examine electrical activity.

OHP treatment induced a significant impairment of the NCV and of 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 demonstrated neuronal atrophy. In addition, OHP induced the development of significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment. Finally, the electrophysiological assessments performed in the spinal cord revealed that, despite the incapacity of the drug to cross the blood-brain barrier, OHP treatment induced a remarkable increase in the activity of the wide dynamic range neurons in the spinal dorsal horn.

Our results demonstrate that the chronic treatment with OHP is able to induce a painful neuropathy in a balb-c mice model. Therefore, this model will enable us to conduct further mechanistic studies of OHP-related antineoplastic activity, peripheral neurotoxicity and pain and can be used as a reference in the preclinical discovery of new neuroprotective as well as of analgesic compounds.

Supported by a grant from the AISAL, Associazione Italiana per le Scienze degli Animali da Laboratorio".

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2011-4384