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.
Pain. 2012 Aug;153(8):1636-1647. doi: 10.1016/j.pain.2012.04.016. Epub 2012 May 30.
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.
奥沙利铂是第三代铂类化疗药物，在治疗晚期转移性结直肠癌方面具有重要意义。其剂量限制的副作用是产生慢性周围神经病变。我们使用改良的奥沙利铂诱导感觉神经病变模型，研究了皮质水平的可塑性变化，作为该模型中疼痛感觉慢性化的潜在机制。使用 DNA 微阵列研究基因表达变化，结果表明，当奥沙利铂处理的动物出现临床神经性疼痛症状，包括机械和热敏感性增加时，感觉皮层中约有 900 个基因下调。由于钾通道在神经元兴奋性中的已知作用，研究进一步集中在这些通道的下调作为皮质过度兴奋的可能分子起源。量化皮质神经元细胞外信号调节激酶 (ERK) 磷酸化的幅度作为神经元活性的标志物，结果表明奥沙利铂处理诱导了 10 倍的增加，表明参与疼痛刺激传递的皮质区域的神经元经历了慢性皮质兴奋性。我们进一步使用针对 Kv2.2 的慢病毒载体 shRNA 进行皮质注射，证明在未处理的动物中下调这种钾通道会导致持续的热和机械性敏感性增加。总之，尽管导致这种皮质兴奋性的确切机制尚不清楚，但我们的研究表明，皮质中钾通道的下调可能是这种化疗诱导的神经性疼痛模型中疼痛慢性化的基础。
