Spinal and Peripheral Mechanisms Individually Lead to the Development of Remifentanil-induced Hyperalgesia
Spinal and Peripheral Mechanisms Individually Lead to the Development of Remifentanil-induced Hyperalgesia
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DOI：
10.1016/j.neuroscience.2020.08.014
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发表时间：
2020-10-15
期刊：
影响因子：
3.3
通讯作者：
Amaya, Fumimasa
中科院分区：
文献类型：
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作者：
Horii, Yasuhiko;Matsuda, Megumi;Amaya, Fumimasa
本研究的目的是确定负责瑞芬太尼诱导的痛觉过敏的神经元位点和个体分子机制。评估甲基纳曲酮（MNX）对瑞芬太尼诱导的行为痛觉过敏的影响，以区分外周和/或中枢神经系统对瑞芬太尼诱导的痛觉过敏的贡献。分析瑞芬太尼输注后背根神经节（DRG）神经元中 p38 丝裂原激活蛋白激酶（p38MAPK）的磷酸化以及 p38MAPK 抑制剂对瑞芬太尼诱导的痛觉过敏的影响，以探讨 p38MAPK 在瑞芬太尼诱导的痛觉过敏的外周机制中的参与。研究了瑞芬太尼输注后脊髓中强啡肽原 mRNA 的水平，以及 BK2 缓激肽受体拮抗剂对瑞芬太尼诱导的痛觉过敏的影响，以评估潜在的脊髓机制。还使用行为分析研究了 MNX 和 BK2 拮抗剂对瑞芬太尼诱导的切口后痛觉过敏恶化的影响。瑞芬太尼输注在输注后早期（4小时至2天）和晚期（8-14天）引起痛觉过敏。 MNX 仅在输注后早期抑制痛觉过敏。在 DRG 神经元中观察到 p38MAPK 磷酸化，p38MAPK 抑制剂在输注后早期抑制痛觉过敏。脊髓中强啡肽原表达增加，BK2 拮抗剂在输注后后期抑制痛觉过敏。 MNX 和 BK2 拮抗剂可抑制瑞芬太尼诱导的切口痛觉过敏加剧。本研究表明，瑞芬太尼激活外周和脊髓神经元，以促进按时间顺序排列的独特的痛觉过敏。 DRG 神经元中的 p38MAPK 磷酸化导致输注后早期外周驱动的痛觉过敏，而脊髓强啡肽-缓激肽信号传导则在输注后后期促进痛觉过敏。 (C) 2020 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of MNX and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 h to 2 days) and late (8-14 days) post-infusion periods. MNX inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.