Joseph Elizabeth K, Chen Xiaojie, Bogen Oliver, Levine Jon D
Department of Medicine, Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440, USA.
J Pain. 2008 May;9(5):463-72. doi: 10.1016/j.jpain.2008.01.335. Epub 2008 Mar 24.
The toxicity profile of oxaliplatin, a platinum derivative currently used in the treatment of colorectal cancer, differs from those of the other platinum compounds, cisplatin and carboplatin. Oxaliplatin treatment induces an acute neurotoxicity characterized by a rapid onset of cold-induced distal dysesthesia and a chronic sensory peripheral neuropathy. A single intravenous dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia and heat and cold allodynia; repeated administration intensified symptoms. A single intradermal dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia. A single dose intravenous oxaliplatin also lowered thresholds and increased responses of C-fiber nociceptors to mechanical stimulation, confirming a peripheral site of action. Whereas peripheral administration of inhibitors of second messengers implicated in models of other painful peripheral neuropathies (PKA, PKC, NO, Ca(2+), and caspase) had no effect; both systemic and local administration of antioxidants (acetyl-L-carnitine, alpha-lipoic acid or vitamin C), all markedly inhibited oxaliplatin-induced hyperalgesia. Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia. We suggest that oxaliplatin acts on IB4 (+)-nociceptors to induce oxidative stress-dependent acute peripheral sensory neuropathy.
Many drugs used to treat cancer produce pain as their dose-limiting side effect. We used a model of this pain syndrome induced by oxaliplatin to demonstrate that pain is produced by action on a subset of nociceptors, the IB4-positive DRG neurons. This information could help define cellular targets against which protective therapies could be developed.
奥沙利铂是一种目前用于治疗结直肠癌的铂类衍生物，其毒性特征与其他铂类化合物顺铂和卡铂不同。奥沙利铂治疗会引发急性神经毒性，其特征为冷诱导的远端感觉异常迅速发作以及慢性感觉性周围神经病变。单次静脉注射奥沙利铂会产生剂量依赖性的机械性痛觉过敏以及热和冷觉异常性疼痛；重复给药会加剧症状。单次皮内注射奥沙利铂会产生剂量依赖性的机械性痛觉过敏。单次静脉注射奥沙利铂还会降低阈值并增加C纤维伤害感受器对机械刺激的反应，证实了其外周作用部位。而在其他疼痛性周围神经病变模型中涉及的第二信使抑制剂（蛋白激酶A、蛋白激酶C、一氧化氮、钙离子和半胱天冬酶）的外周给药没有效果；抗氧化剂（乙酰-L-肉碱、α-硫辛酸或维生素C）的全身和局部给药均能显著抑制奥沙利铂诱导的痛觉过敏。鞘内注射针对IB4阳性伤害感受器的神经毒素IB4-皂草素，可显著减弱脊髓背角的IB4染色，并完全预防奥沙利铂诱导的痛觉过敏。我们认为奥沙利铂作用于IB4（+）伤害感受器，以诱导氧化应激依赖性急性外周感觉神经病变。
许多用于治疗癌症的药物会产生疼痛作为其剂量限制性副作用。我们使用奥沙利铂诱导的这种疼痛综合征模型来证明疼痛是由作用于一部分伤害感受器，即IB4阳性背根神经节神经元产生的。这些信息有助于确定可开发保护性治疗的细胞靶点。
