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HCN2 contributes to oxaliplatin-induced neuropathic pain by inducing spinal long-term potentiation via activation of NMDA receptor-mediated CaMKII signaling.
Brain Research Bulletin ( IF 3.8 ) Pub Date : 2020-03-09 , DOI: 10.1016/j.brainresbull.2020.03.008
Xiaoyu Liu 1 , Qing Ji 1 , Fangfang Liu 1 , Li Jin 1 , Yuanhui Tan 1 , Lidong Zhang 1 , Jun Tang 1
Affiliation  

Our previous findings indicate that HCN2 contributes to oxaliplatin-induced neuropathic pain, but the mechanisms underlying the development of neuropathic pain are still unclear. Here, we found that the rat HCN2 levels significantly increased after high-frequency stimulation-induced long-term potentiation (LTP). Spinal local application of ZD7288 (a cyclic-nucleotide-gated-channel-specific inhibitor) prevented LTP induction after intraperitoneal injection of oxaliplatin. In addition, oxaliplatin administration induced spinal LTP via activation of the CaMKII-CREB cascade in the rat spinal dorsal horn. Moreover, we found that administration of oxaliplatin significantly increased the amplitude of excitatory postsynaptic currents and the number of action potentials, but these effects were attenuated by pretreatment with either CaMKII inhibitor KN-93 or NR2B antagonist Ro 25-6981. An increase in the phosphorylation of spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1) after oxaliplatin administration was weakened by ZD7288 pretreatment. Administration of noncompetitive NMDA receptor antagonist MK-801 blocked oxaliplatin-evoked CaMKII-CREB cascade activation and prevented HCN2-mediated spinal-LTP induction in vitro and suppressed neuropathic-pain behaviors of rats. All these data suggest that HCN2 contributes to the development of neuropathic pain by inducing spinal LTP via activation of NMDA receptor-mediated CaMKII signaling.

中文翻译:

HCN2 通过激活 NMDA 受体介导的 CaMKII 信号传导诱导脊髓长期增强,从而导致奥沙利铂诱导的神经性疼痛。

我们之前的研究结果表明 HCN2 有助于奥沙利铂诱导的神经性疼痛,但神经性疼痛发展的潜在机制仍不清楚。在这里,我们发现高频刺激诱导的长时程增强(LTP)后大鼠 HCN2 水平显着增加。ZD7288(一种环核苷酸门控通道特异性抑制剂)的脊髓局部应用阻止了奥沙利铂腹腔注射后的 LTP 诱导。此外,奥沙利铂给药通过激活大鼠脊髓背角中的 CaMKII-CREB ​​级联反应诱导脊髓 LTP。此外,我们发现奥沙利铂的给药显着增加了兴奋性突触后电流的幅度和动作电位的数量,但这些影响通过 CaMKII 抑制剂 KN-93 或 NR2B 拮抗剂 Ro 25-6981 的预处理减弱。ZD7288 预处理减弱了奥沙利铂给药后脊髓 N-甲基-d-天冬氨酸 (NMDA) 受体亚基 1 (NR1) 磷酸化的增加。非竞争性 NMDA 受体拮抗剂 MK-801 的给药阻断了奥沙利铂诱发的 CaMKII-CREB ​​级联激活,并在体外阻止了 HCN2 介导的脊髓 LTP 诱导,并抑制了大鼠的神经性疼痛行为。所有这些数据表明,HCN2 通过激活 NMDA 受体介导的 CaMKII 信号传导诱导脊髓 LTP,从而促进神经性疼痛的发展。ZD7288 预处理减弱了奥沙利铂给药后脊髓 N-甲基-d-天冬氨酸 (NMDA) 受体亚基 1 (NR1) 磷酸化的增加。非竞争性 NMDA 受体拮抗剂 MK-801 的给药阻断了奥沙利铂诱发的 CaMKII-CREB ​​级联激活,并在体外阻止了 HCN2 介导的脊髓 LTP 诱导,并抑制了大鼠的神经性疼痛行为。所有这些数据表明,HCN2 通过激活 NMDA 受体介导的 CaMKII 信号传导诱导脊髓 LTP,从而促进神经性疼痛的发展。ZD7288 预处理减弱了奥沙利铂给药后脊髓 N-甲基-d-天冬氨酸 (NMDA) 受体亚基 1 (NR1) 磷酸化的增加。非竞争性 NMDA 受体拮抗剂 MK-801 的给药阻断了奥沙利铂诱发的 CaMKII-CREB ​​级联激活,并在体外阻止了 HCN2 介导的脊髓 LTP 诱导,并抑制了大鼠的神经性疼痛行为。所有这些数据表明,HCN2 通过激活 NMDA 受体介导的 CaMKII 信号传导诱导脊髓 LTP,从而促进神经性疼痛的发展。
更新日期:2020-03-09
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