Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin
Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin
复制标题
脑脊液奥沙利铂会导致奥沙利铂全身给药引起的急性疼痛
DOI：
10.1097/aln.0000000000001084
复制
发表时间：
2016-05-01
期刊：
影响因子：
8.8
通讯作者：
Xin, Wen-Jun
中科院分区：
文献类型：
--
作者：
Huang, Zhen-Zhen;Li, Dai;Xin, Wen-Jun
背景：由于奥沙利铂在脑脊液（CSF）中的浓度有限，全身给药奥沙利铂对中枢神经系统（CNS）肿瘤没有影响，而临床报道奥沙利铂可诱发急性脑病。目前，奥沙利铂全身给药后CNS中神经元功能的损害尚未研究。方法：大鼠腹腔注射奥沙利铂（4 mg/kg）后，采用vonFrey试验和足底试验评价神经病理性疼痛行为。应用电感耦合等离子体质谱、电生理记录、实时定量逆转录聚合酶链反应、染色质免疫沉淀、Western印迹、免疫组织化学和小干扰RNA来了解其机制。结果：奥沙利铂单次给药后，CSF中奥沙利铂的浓度呈时间依赖性增加。检测浓度（6.6 nM）的奥沙利铂脊髓应用显著增加了背角的场电位，诱导了急性机械异常性疼痛（各n = 12）和热痛觉过敏（各n = 12），并增强了投射神经激肽1受体表达层I至II神经元中诱发的兴奋性突触后电流和自发兴奋性突触后电流。作者进一步发现奥沙利铂显著增加了cx 3cl 1启动子区的核因子- B p65结合和组蛋白H4乙酰化。因此，上调的脊髓CX 3CL 1显著介导奥沙利铂给药后中枢致敏和急性疼痛行为的诱导。结论：本研究的结果表明，CSF中的奥沙利铂可能直接损害中枢神经元的正常功能，并有助于化疗期间CNS相关副作用的快速发展。这为预防奥沙利铂诱导的急性疼痛性神经病变和脑病提供了新的靶点。
Background:Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. Methods:The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma–mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. Results:Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor–expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-&kgr;B p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. Conclusions:The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.