Department of Anesthesiology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China; Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Gulin, Guangxi, 541004, China.
Department of Anesthesiology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei, 434020, China; Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Gulin, Guangxi, 541004, China.
Eur J Pharmacol. 2020 Feb 15;869:172882. doi: 10.1016/j.ejphar.2019.172882. Epub 2019 Dec 19.
Remifentanil, ultra-short-acting μ-opioid receptor agonist, has the greatest advantage in analgesia but could increase postoperative pain scores and induces postoperative hyperalgesia. Dezocine is a mixed opioid receptor partial agonist/antagonist and has been used for postoperative hyperalgesia management in clinical patients,but the potential molecular mechanism is still unclear. Ca/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ) has been reported involved in remifentanil-induced hyperalgesia (RIH) in previous studies, but the relationship between CaMKⅡ and dezocine in RIH is still unclear. To investigate the mechanism of dezocine in RIH, we used a remifentanil induced postoperative hyperalgesia (RIPH) in incisional pain model of mouse. We subcutaneously infused remifentanil (40 μg/kg) to induce postoperative hyperalgesia. Dezocine (1.5 mg/kg, 3.0 mg/kg, and 6.0 mg/kg) was infused subcutaneously with remifentanil using the apparatus pump for 30 min. Paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were used to assess thermal hyperalgesia and mechanical allodynia. Western blotting analysis and immunohistochemistry analysis were used to assess the expression of phosphorylated CaMKⅡα (p-CaMKⅡα) in somatosensory cortex, hippocampus and spinal cord. Subcutaneous infusion of remifentanil enhanced postoperative pain induced by surgical incision and increased PWTL and PWMT. Dezocine dose-dependently decreased the PWTL and PWMT in RIPH model. Correlating with behavioral effects, dezocine inhibited remifentanil-induced up-regulation of p-CaMKⅡα expression in somatosensory cortex, hippocampus and spinal cord. Dezocine could attenuate RIPH by suppressing p-CaMKⅡα.
瑞芬太尼，一种超短效 μ 阿片受体激动剂，在镇痛方面具有最大优势，但会增加术后疼痛评分并引起术后痛觉过敏。地佐辛是一种混合阿片受体部分激动剂/拮抗剂，已在临床患者的术后痛觉过敏管理中使用，但潜在的分子机制尚不清楚。钙/钙调蛋白依赖性蛋白激酶 Ⅱ（CaMKⅡ）在以前的研究中已被报道参与瑞芬太尼诱导的痛觉过敏（RIH），但 CaMKⅡ与地佐辛在 RIH 中的关系仍不清楚。为了研究地佐辛在 RIH 中的作用机制，我们使用了一种瑞芬太尼诱导的切口痛模型中的术后痛觉过敏（RIPH）的小鼠模型。我们通过皮下输注瑞芬太尼（40μg/kg）来诱导术后痛觉过敏。使用仪器泵在皮下输注地佐辛（1.5mg/kg、3.0mg/kg 和 6.0mg/kg）30 分钟。通过足底撤回热潜伏期（PWTL）和足底撤回机械阈值（PWMT）评估热痛觉过敏和机械性痛觉过敏。Western blot 分析和免疫组织化学分析用于评估感觉皮层、海马体和脊髓中磷酸化 CaMKⅡα（p-CaMKⅡα）的表达。皮下输注瑞芬太尼增强了手术切口引起的术后疼痛，并增加了 PWTL 和 PWMT。地佐辛剂量依赖性地降低了 RIPH 模型中的 PWTL 和 PWMT。与行为效应相关，地佐辛抑制了瑞芬太尼诱导的感觉皮层、海马体和脊髓中 p-CaMKⅡα表达的上调。地佐辛通过抑制 p-CaMKⅡα 来减轻 RIPH。
