Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats.
Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats.
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DOI：
10.1186/1744-8069-7-8
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发表时间：
2011-01-20
期刊：
影响因子：
3.3
通讯作者：
Oishi R
中科院分区：
文献类型：
--
作者：
Mihara Y;Egashira N;Sada H;Kawashiri T;Ushio S;Yano T;Ikesue H;Oishi R
奥沙利铂是一种以铂为基础的化疗药物，其特征是发生急性和慢性周围神经病变。慢性神经病是一种剂量限制性毒性。我们先前报道了奥沙利铂重复给药在大鼠早期诱导冷痛觉过敏，在晚期诱导机械性异常性疼痛。在本研究中，我们研究了含NR 2B的N-甲基-D-天冬氨酸（NMDA）受体参与奥沙利铂诱导的大鼠机械性异常性疼痛。重复施用奥沙利铂（4 mg/kg，i. p.，鞘内注射NMDA受体拮抗剂MK-801（10 nmol）和美金刚胺（1 μmol）可逆转机械性痛觉超敏。类似地，选择性NR 2B拮抗剂Ro 25 -6981（300 nmol，i. t.）和艾芬地尔（50 mg/kg，p.o.）显著减弱奥沙利铂诱导的疼痛行为。此外，奥沙利铂在第25天（晚期）增加了大鼠脊髓中NR 2B蛋白和mRNA的表达，但在第5天（早期）未增加。此外，我们研究了一氧化氮合酶（NOS）作为NMDA受体的下游靶点的参与。非选择性NOS抑制剂L-NAME和神经元NOS（nNOS）抑制剂7-硝基吲唑可显著抑制奥沙利铂诱导的痛行为。奥沙利铂使脊髓背角浅层NOS组织化学标记物NADPH黄递酶染色强度明显增加，鞘内注射Ro 25 -6981可逆转这种增加的强度。这些结果表明，脊髓含NR 2B的NMDA受体参与奥沙利铂诱导的机械性异常性疼痛。
Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats. Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981. These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.
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