Cortical effect of oxaliplatin associated with sustained neuropathic pain: exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex.
Oxaliplatin is a third-generation platinum-based chemotherapy drug that has gained importance in the treatment of advanced metastatic colorectal cancer. Its dose-limiting side effect is the production of chronic peripheral neuropathy. Using a modified model of oxaliplatin-induced sensory neuropathy, we investigated plastic changes at the cortical level as possible mechanisms underlying the chronicity of pain sensation in this model. Changes in gene expression were studied using DNA microarray which revealed that when oxaliplatin-treated animals displayed clinical neuropathic pain symptoms, including mechanical and thermal hypersensitivity, approximately 900 were down-regulated in the somatosensory cortex. Because of the known role of potassium channels in neuronal excitability, the study further focussed on the down-regulation of these channels as the possible molecular origin of cortical hyperexcitability. Quantification of the magnitude of neuronal extracellular signal-regulated kinase (ERK) phosphorylation in cortical neurons as a marker of neuronal activity revealed a 10-fold increase induced by oxaliplatin treatment, suggesting that neurons of cortical areas involved in transmission of painful stimuli undergo a chronic cortical excitability. We further demonstrated, using cortical injection of lentiviral vector shRNA against Kv2.2, that down-regulation of this potassium channel in naive animals induced a sustained thermal and mechanical hypersensitivity. In conclusion, although the detailed mechanisms leading to this cortical excitability are still unknown, our study demonstrated that a cortical down regulation of potassium channels could underlie pain chronicity in this model of chemotherapy-induced neuropathic pain.
Laboratoire de Neurobiologie, CNRS UMR 7637, Ecole Supérieure de Physique et de Chimie Industrielles, 10 rue Vauquelin, 75005 Paris, France Equipe de Statistique Appliquée, Ecole Supérieure de Physique et de Chimie Industrielles, 10 rue Vauquelin, 75005 Paris, France.
Karine
K
Thibault
Bernard
B
Calvino
Sophie
S
Dubacq
Marie
M
Roualle-de-Rouville
Vallier
V
Sordoillet
Isabelle
I
Rivals
Sophie
S
Pezet
D000818:Animals; D000970:Antineoplastic Agents; D059350:Chronic Pain / Q000139:chemically induced* / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D009437:Neuralgia; D009473:Neuronal Plasticity / Q000187:drug effects*; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology*; D014018:Tissue Distribution / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D051669:Shab Potassium Channels; D000077150:Oxaliplatin