Xie Jing-Dun, Chen Shao-Rui, Chen Hong, Zeng Wei-An, Pan Hui-Lin
From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and
J Biol Chem. 2016 Sep 9;291(37):19364-73. doi: 10.1074/jbc.M116.732347. Epub 2016 Jul 25.
Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices. In paclitaxel-treated rats, the baseline frequency of miniature EPSCs (mEPSCs) was significantly increased; the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) completely normalized this frequency. Also, AP5 significantly reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation and reversed the reduction in the paired-pulse ratio of evoked EPSCs in paclitaxel-treated rats. Blocking GluN2A-containing, but not GluN2B-containing, NMDARs largely decreased the frequency of mEPSCs and the amplitude of evoked EPSCs of dorsal horn neurons in paclitaxel-treated rats. Furthermore, inhibition of protein kinase C fully reversed the increased frequency of mEPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats. Paclitaxel treatment significantly increased the protein level of GluN2A and phosphorylated GluN1 in the dorsal root ganglion. In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.
疼痛性周围神经病变是紫杉醇（泰素）等化疗药物的一种严重不良反应。谷氨酸N-甲基-D-天冬氨酸受体（NMDARs）在与神经性疼痛相关的突触可塑性中起关键作用。然而，紫杉醇治疗并不会改变脊髓背角神经元的突触后NMDAR活性。在本研究中，我们通过记录脊髓切片中背角神经元的兴奋性突触后电流（EPSCs），来确定紫杉醇是否影响突触前NMDAR活性。在接受紫杉醇治疗的大鼠中，微小兴奋性突触后电流（mEPSCs）的基线频率显著增加；NMDAR拮抗剂2-氨基-5-磷酸戊酸（AP5）使该频率完全恢复正常。此外，AP5显著降低了背根刺激诱发的单突触EPSCs的幅度，并逆转了紫杉醇治疗大鼠中诱发EPSCs配对脉冲比率的降低。阻断含GluN2A而非含GluN2B的NMDARs，在很大程度上降低了紫杉醇治疗大鼠背角神经元mEPSCs的频率和诱发EPSCs的幅度。此外，抑制蛋白激酶C完全逆转了紫杉醇治疗大鼠中mEPSCs频率的增加和诱发EPSCs的幅度。紫杉醇治疗显著增加了背根神经节中GluN2A和磷酸化GluN1的蛋白水平。此外，鞘内注射AP5或美金刚的全身给药显著减轻了紫杉醇诱导的疼痛超敏反应。我们的研究结果表明，紫杉醇治疗通过蛋白激酶C诱导脊髓中突触前NMDARs的强直性激活，以增强来自初级传入神经的伤害性输入。在脊髓水平靶向突触前NMDARs可能是治疗化疗诱导的神经性疼痛的有效策略。
