title: Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice.
abstract: BACKGROUND
  A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice
  
  
  RESULTS
  We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.
  
  
  CONCLUSIONS
  Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.
authors.affiliation: School of Nursing, Center for Pain Studies, University of Maryland, Baltimore, MD, USA. renn@son.umaryland.edu
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Renn
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Carozzi
authors.forename: Peter
authors.initials: P
authors.lastname: Rhee
authors.forename: Danisha
authors.initials: D
authors.lastname: Gallop
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009431:Neural Conduction / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010146:Pain / Q000139:chemically induced* / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin