Liu Aifen, Wang Xiaopeng, Wang Hui, Lv Guoyi, Li Yize, Li Hongmei
Department of Anesthesiology, The Second Hospital Affiliated to Tianjin Medical University, Tianjin 300042, P.R. China.
Department of Anesthesiology, Shanxi Academy of Medical Science, Shanxi Dayi Hospital, Taiyuan, Shanxi 030032, P.R. China.
Exp Ther Med. 2018 Feb;15(2):2140-2147. doi: 10.3892/etm.2017.5652. Epub 2017 Dec 18.
The interaction of remifentanil with glutamate systems has an important role in remifentanil-induced thermal and mechanical hyperalgesia. A previous study by our group suggested that the trafficking and function of glutamate receptor 1 (GluR1) subunits contributes to remifentanil-induced hyperalgesia by regulating the phosphorylation of GluR1 in dorsal horn neurons. The present study demonstrated that δ opioid receptor (DOR) inhibition prevented thermal and mechanical hyperalgesia, which was induced by remifentanil infusion via attenuating GluR1 subunit trafficking and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function in dorsal horn neurons. Sprague Dawley rats received a plantar incision and remifentanil infusion to induce a model of postoperative hyperalgesia. Thermal and mechanical pain was tested at 8 different time-points. Expression of AMPAR subunits GluR1 and DOR, as well as the phosphorylation status of GluR1 were evaluated by western blot analysis. Furthermore, the function of AMPAR in the spinal dorsal horn was measured by whole-cell patch-clamp recording. Remifentanil-induced thermal and mechanical hyperalgesia appeared after the 60-min infusions, reaching a peak level on day 2 and persisting for 5 days. Remifentanil infusion led to upregulation of membrane expression of the AMPAR subunit GluR1 and DOR (P=0.003 and 0.001, respectively) no change in total GluR1 and DOR expression levels (P=0.244 and 0.531, respectively). Selective DOR inhibitor naltrindole caused a reduction of remifentanil-induced hyperalgesia, which was accompanied by downregulation of membrane levels of GluR1 in the spinal cord (P=0.0013). In addition, DOR inhibition led to downregulation of GluR1 phosphorylated at Ser845. Furthermore, the AMPAR-mediated miniature excitatory post-synaptic current was increased in frequency and in amplitude in dorsal horn neurons (P=0.002 and 0.0011, respectively), which was decreased by incubation with naltrindole. Combined behavioral, western blot and electrophysiological evidence indicated that remifentanil-induced hyperalgesia was mediated by DOR activation, followed by phosphorylation-dependent GluR1 trafficking and AMPAR function enhancement in the spinal cord. DOR appears to be required for remifentanil and incision-induced hyperalgesia development and to be a potential biochemical target for treating opioid-induced postoperative hyperalgesia.
瑞芬太尼与谷氨酸系统的相互作用在瑞芬太尼诱导的热痛觉过敏和机械性痛觉过敏中起重要作用。我们团队之前的一项研究表明，谷氨酸受体1（GluR1）亚基的转运和功能通过调节背角神经元中GluR1的磷酸化，促成了瑞芬太尼诱导的痛觉过敏。本研究表明，δ阿片受体（DOR）抑制可预防热痛觉过敏和机械性痛觉过敏，这是通过减弱背角神经元中GluR1亚基的转运和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的功能，由瑞芬太尼输注诱导产生的。将Sprague Dawley大鼠进行足底切口并输注瑞芬太尼，以诱导术后痛觉过敏模型。在8个不同时间点测试热痛觉和机械性疼痛。通过蛋白质免疫印迹分析评估AMPAR亚基GluR1和DOR的表达，以及GluR1的磷酸化状态。此外，通过全细胞膜片钳记录测量脊髓背角中AMPAR的功能。瑞芬太尼诱导的热痛觉过敏和机械性痛觉过敏在输注60分钟后出现，在第2天达到峰值水平并持续5天。瑞芬太尼输注导致AMPAR亚基GluR1和DOR的膜表达上调（分别为P = 0.003和0.001），而GluR1和DOR的总表达水平无变化（分别为P = 0.244和0.531）。选择性DOR抑制剂纳曲吲哚可减轻瑞芬太尼诱导的痛觉过敏，同时伴有脊髓中GluR1膜水平的下调（P = 0.0013）。此外，DOR抑制导致Ser845位点磷酸化的GluR1下调。此外，背角神经元中AMPAR介导的微小兴奋性突触后电流在频率和幅度上均增加（分别为P = 0.002和0.001），而与纳曲吲哚孵育后该电流减小。行为学、蛋白质免疫印迹和电生理学的综合证据表明瑞芬太尼诱导的痛觉过敏是由DOR激活介导的，随后是脊髓中磷酸化依赖性的GluR1转运和AMPAR功能增强。DOR似乎是瑞芬太尼和切口诱导的痛觉过敏发展所必需的，并且是治疗阿片类药物诱导的术后痛觉过敏的潜在生化靶点。
