Role of mitochondrial Ca(2+) uniporter in remifentanil-induced postoperative allodynia.
Role of mitochondrial Ca(2+) uniporter in remifentanil-induced postoperative allodynia.
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线粒体 Ca(2) 单向转运蛋白在瑞芬太尼诱发的术后异常性疼痛中的作用。
DOI：
10.1111/ejn.13842
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发表时间：
2018
影响因子：
3.4
通讯作者：
Xu Shiyuan
中科院分区：
文献类型：
--
作者：
Lu Aizhu;Lei Hongyi;Li Le;Lai Luying;Liang Wenbin;Xu Shiyuan
阿片类药物引起的痛觉过敏（OIH）和异常性疼痛是一种众所周知的现象，是指患者长期接触阿片类药物后的疼痛过敏。 OIH 限制了阿片类药物在疼痛控制中的使用，但其潜在机制尚不完全清楚。本研究调查了线粒体 Ca2+ 单向转运蛋白 (MCU) 在瑞芬太尼（一种常用的阿片类镇痛药）引起的异常性疼痛中的作用。使用 OIH 大鼠模型，我们发现用特定的 MCU 拮抗剂 Ru360 预处理可显着减弱切口和瑞芬太尼引起的机械性异常性疼痛，这表明 MCU 在切口和阿片类药物引起的异常性疼痛中发挥着关键作用。此外，脊柱组织中 Rhod-2（一种线粒体 Ca2+ 染料）的成像研究表明，切开和瑞芬太尼输注后，线粒体 Ca2+ 水平增加，而 Ru360 减弱了这一水平。蛋白质印迹和免疫组织化学显示，pNR（磷酸化 N-甲基-D-天冬氨酸（NMDA）受体）和 pERK（磷酸化细胞外信号调节激酶）在切口诱导的痛觉过敏和瑞芬太尼诱导的痛觉过敏期间均增加，并且 Ru360 再次显着减弱 pNR 和 pERK 的增加。总之，我们的数据表明，MCU 在瑞芬太尼引起的术后机械异常性疼痛中发挥着关键作用，NMDA 受体和 ERK 可能是下游效应器。我们的研究结果为瑞芬太尼引起的机械性异常性疼痛提供了新的机制，并鼓励未来研究线粒体 Ca2+ 单向转运蛋白作为预防 OIH 的潜在治疗靶点。
Opioid‐induced hyperalgesia (OIH) and allodynia is a well‐known phenomenon and refers to the pain sensitization in patients after prolonged opioid exposure. OIH limits the use of opioids in pain control, but the underlying mechanisms are not fully clear. This study investigated the role of mitochondrial Ca2+uniporter (MCU) in remifentanil (a commonly used opioid analgesic)‐induced allodynia. Using a rat model of OIH, we found that incision‐ and remifentanil‐induced mechanical allodynia were remarkably attenuated by pretreatment with Ru360, a specific MCU antagonist, suggesting a critical role of MCU in both incision‐ and opioid‐induced allodynia. In addition, imaging studies with Rhod‐2 (a mitochondrial Ca2+dye) in spinal tissues demonstrated increased mitochondrial Ca2+level in response to incision and remifentanil infusion, which was attenuated by Ru360. Western blot and immunohistochemistry showed that pNR [phosphorylated N‐methyl‐D‐aspartate (NMDA) receptor] and pERK (phosphorylated extracellular signal‐regulated kinase) are increased during both incision‐induced hyperalgesia and remifentanil‐induced hyperalgesia, and again the increases in pNR and pERK were remarkably attenuated by Ru360. Together, our data demonstrate that MCU plays a critical role in remifentanil‐induced postoperative mechanical allodynia, with NMDA receptor and ERK as possible downstream effectors. Our findings provide novel mechanisms for remifentanil‐induced mechanical allodynia and encourage future studies to examine the mitochondrial Ca2+uniporter as a potential therapeutic target for prevention of OIH.