Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords
Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords
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DOI：
10.1113/jphysiol.2013.263814
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发表时间：
2014-01-01
影响因子：
5.5
通讯作者：
Pan, Hui-Lin
中科院分区：
文献类型：
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作者：
Chen, Shao-Rui;Hu, Yi-Min;Pan, Hui-Lin
钙调磷酸酶抑制剂，如环孢素A和他克莫司（FK 506），在保存同种异体移植物功能中发挥了关键作用。然而，这些药物可能会导致患者出现无法解释的剧烈疼痛，通常被称为钙调神经磷酸酶诱导的疼痛综合征（CIPS）。虽然钙调神经磷酸酶可以调节NMDA受体（NMDAR）的活性，脊髓突触可塑性和CIPS之间的因果关系仍然未知。在本研究中，我们发现大鼠全身给予FK 506（1.5 mg/kg/天）持续7天可导致持久的伤害性和机械性超敏反应。脊髓切片全细胞膜片钳记录显示，FK 506处理引起背根刺激诱发的背角神经元NMDAR介导的兴奋性突触后电流（EPSC）幅度大幅增加。FK 506给药组大鼠通过喷NMDA应用于背角神经元引起的NMDAR电流幅度也显著高于溶剂给药组大鼠。在FK 506处理的大鼠中，大多数背角神经元中自发和微型EPSC的频率显著增加，并通过阻断NMDAR而降低。此外，阻断GluN 2A或GluN 2B亚基同样降低了FK 506处理大鼠背角神经元中诱发EPSC的幅度和微型EPSC的频率。此外，鞘内注射NMDAR拮抗剂或全身给予美金刚可有效逆转FK 506给药大鼠的伤害性和机械性超敏反应。我们的研究结果表明，钙调磷酸酶抑制通过增强脊髓突触前和突触后NMDAR活性增加谷氨酸介导的伤害性输入。NMDAR拮抗剂可能是治疗CIPS的一种新的治疗选择。
Calcineurin inhibitors, such as cyclosporin A and tacrolimus (FK506), have played a pivotal role in the preservation of allograft function. However, these drugs can cause unexplained severe pain in patients, often referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin can regulate NMDA receptor (NMDAR) activity, the causal relationship between spinal synaptic plasticity and CIPS remains unknown. In this study, we showed that systemic administration of FK506 (1.5 mg kg(-1) day(-1)) for 7 days in rats led to long-lasting nociceptive and mechanical hypersensitivity. Whole-cell patch-clamp recordings in spinal cord slices revealed that FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation. The amplitude of NMDAR currents elicited by puff NMDA application to dorsal horn neurons was also significantly greater in FK506-treated than in vehicle-treated rats. The frequency of spontaneous and miniature EPSCs in most dorsal horn neurons was profoundly increased in FK506-treated rats and was reduced by blocking NMDARs. Furthermore, blocking GluN2A or GluN2B subunits similarly reduced the amplitude of evoked EPSCs and the frequency of miniature EPSCs in dorsal horn neurons of FK506-treated rats. In addition, intrathecal injection of an NMDAR antagonist or systemic administration of memantine effectively reversed nociceptive and mechanical hypersensitivity in FK506-treated rats. Our findings indicate that calcineurin inhibition increases glutamate-mediated nociceptive input by potentiating presynaptic and postsynaptic NMDAR activity in spinal cords. NMDAR antagonists may represent a new therapeutic option for the treatment of CIPS.