Intrathecal Injection of the Peptide Myr-NR2B9c Attenuates Bone Cancer Pain Via Perturbing N-Methyl-D-Aspartate Receptor-PSD-95 Protein Interactions in Mice
Intrathecal Injection of the Peptide Myr-NR2B9c Attenuates Bone Cancer Pain Via Perturbing N-Methyl-D-Aspartate Receptor-PSD-95 Protein Interactions in Mice
复制标题
鞘内注射肽 Myr-NR2B9c 通过扰乱小鼠 N-甲基-D-天冬氨酸受体-PSD-95 蛋白相互作用减轻骨癌疼痛
DOI：
10.1213/ane.0000000000000202
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发表时间：
2014-06-01
影响因子：
5.7
通讯作者：
Gu, Xiaoping
中科院分区：
文献类型：
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作者：
Liu, Yue;Cui, Xinlong;Gu, Xiaoping
背景：N-甲基-D-天冬氨酸受体（NMDAR）依赖性中枢敏化在癌痛中发挥重要作用。突触后密度蛋白 95 (PSD-95) 与 NMDAR 亚基 2B (NR2B) 的结合可以将 NMDAR 活性与细胞内酶（例如神经元一氧化氮合酶 (nNOS)）耦合，促进下游信号传导通路，并调节 NMDAR 稳定性，从而有助于突触可塑性。在这项研究中，我们研究了使用肽模拟策略扰乱含有 NR2B 的脊髓 NMDAR 和 PSD-95 之间的特异性相互作用是否可以减轻骨癌相关的疼痛行为。方法：将骨肉瘤细胞植入C3H/HeJ小鼠右侧股骨髓内间隙，诱导进行性骨癌相关疼痛行为。应用蛋白质印迹法检测脊髓磷酸化 Tyr1472 NR2B、nNOS 和 PSD-95 的表达。我们进一步研究了鞘内注射模拟肽 Myr-NR2B9c（竞争性破坏 PSD-95 和 NR2B 之间的相互作用）对伤害感受行为以及对与脊髓骨癌疼痛相关的磷酸-Tyr1472 NR2B、nNOS 和 PSD-95 上调的影响。结果：接种骨肉瘤细胞可诱导进行性骨癌疼痛，并导致磷酸-Tyr1472 NR2B、nNOS 和 PSD-95 显着上调。鞘内注射 Myr-NR2B9c 可减轻骨癌引起的机械异常性疼痛、热痛觉过敏，并减少脊髓磷酸化 Tyr1472 NR2B、nNOS 和 PSD-95 表达。结论：鞘内注射 Myr-NR2B9c 可减轻骨癌疼痛。脊髓 NR2B 的内化和下游 nNOS 信号传导中包含 NR2B 的 NMDAR 激活的解离可能有助于 Myr-NR2B9c 的镇痛作用。这种方法可以避免与阻断 NMDAR 相关的负面后果，并且可能是治疗骨癌疼痛的新策略。
BACKGROUND:N-methyl-D-aspartate receptor (NMDARs)-dependent central sensitization plays an important role in cancer pain. Binding of NMDAR subunit 2B (NR2B) by postsynaptic density protein-95 (PSD-95) can couple NMDAR activity to intracellular enzymes, such as neuronal nitric oxide synthase (nNOS), facilitate downstream signaling pathways, and modulate NMDAR stability, contributing to synaptic plasticity. In this study, we investigated whether perturbing the specific interaction between spinal NR2B-containing NMDAR and PSD-95, using a peptide-mimetic strategy, could attenuate bone cancer-related pain behaviors. METHODS:Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer-related pain behaviors. Western blotting was applied to examine the expression of spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95. We further investigated the effects of intrathecal injection of the mimetic peptide Myr-NR2B9c, which competitively disrupts the interaction between PSD-95 and NR2B, on nociceptive behaviors and on the upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95 associated with bone cancer pain in the spinal cord. RESULTS:Inoculation of osteosarcoma cells induced progressive bone cancer pain and resulted in a significant upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95. Intrathecal administration of Myr-NR2B9c attenuated bone cancer-evoked mechanical allodynia, thermal hyperalgesia, and reduced spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95 expression. CONCLUSIONS:Intrathecal administration of Myr-NR2B9c reduced bone cancer pain. Internalization of spinal NR2B and dissociation NR2B-containing NMDARs activation from downstream nNOS signaling may contribute to the analgesic effects of Myr-NR2B9c. This approach may circumvent the negative consequences associated with blocking NMDARs, and may be a novel strategy for the treatment of bone cancer pain.