淫羊藿素联合吗啡对骨癌痛小鼠的镇痛效应研究

Analgesic effect of Icaritin combined with morphine on the bone cancer pain in mice

摘要:

目的：探究淫羊藿素 (icartin, ICT) 对骨癌痛 (bone cancer pain, BCP) 小鼠的镇痛效应，以及淫羊藿素与吗啡联合用药的镇痛效应；确定半效剂量淫羊藿素与吗啡联合用药，在达到吗啡最大镇痛效应时所减少的吗啡用量。方法：采用雄性 C57BL/6J 小鼠及路易斯（Lewis）肺癌细胞建立 BCP小鼠模型。通过测定机械刺激缩足阈值 (paw withdrawal threshold, PWT)、冷刺激缩足潜伏期 (paw withdrawal latency, PWL) 以及自发抬足次数和抬足保护时间以评估小鼠疼痛敏感度。结果：自造模后第7~14天起，BCP小鼠左侧（荷瘤侧）后爪PWT和PWL明显降低，自发抬足次数和抬足保护时间明显上升，并持续存在 (P < 0.05)，表明BCP小鼠造模成功。在造模后第7~14天给予淫羊藿素，自第10~14天起淫羊藿素明显增加BCP小鼠左侧后爪的PWT和PWL，并减少自发抬足次数和抬足保护时间，停药后效应持续至造模后第18天（即停药后第4天）（P < 0.05），表明淫羊藿素对骨癌痛小鼠具有明显的镇痛效应。此外，应用全效剂量（2× EC50）淫羊藿素（200 mg/kg）与吗啡联合用药，可以明显延长停药后镇痛效应，镇痛效应持续至造模后第21天（即停药后第7天）（P < 0.05）。应用半效剂量（1× EC50）淫羊藿素（100 mg/kg）与吗啡联合用药，在达到吗啡最佳镇痛效应时最多可减少60%的吗啡用量。结论：淫羊藿素对BCP小鼠有明显的镇痛效应；淫羊藿素与吗啡联合用药可明显延长停药后镇痛效应，并可减少60%的吗啡用量。

Abstract:

Objective: To investigate the analgesic effect of icaritin on bone cancer pain (BCP) in mice, and the potential synergistic analgesic effect of icaritin combined with morphine. Moreover, to determine the amount of morphine reduced when the maximum analgesic effect of morphine was achieved by using icariin (at a half-effect dose) in combination with morphine. Methods: Male C57BL/6 mice and Lewis lung cancer (LLC) cells were applied to establish a mice model of BCP. The pain threshold of mice was assessed by measuring the paw withdrawal threshold (PWT) in response to mechanical stimulation, the paw withdrawal latency (PWL) in response to cold stimulation, the times of spontaneous flinches and the time spent guarding. Results: From the 7th and 14th days after modeling, the PWT and PWL of ipsilateral (tumor-bearing) hind-paw in BCP mice decreased significantly, while the times of spontaneous flinches and the time spent guarding were significantly increased and persisted (P < 0.05), indicating the establishment of BCP mice model was successful. Then, icaritin was administered to BCP mice from the 7th to the 14th day after modeling. The results revealed that starting from the 10th to the 14th day, icaritin significantly increased the PWT and PWL of the ipsilateral hind-paw in BCP model mice, and reduced the times of spontaneous flinches and the time spent guarding of BCP model mice. These analgesic effects lasted until the 18th day after surgery (i.e., the 4th day after drug discontinuation) (P < 0.05), suggesting that icaritin has a significant analgesic effect on BCP model mice. When icaritin was administered at a dose of 2× EC50 (200 mg/kg) in combination with morphine, it significantly prolonged the post-analgesic effects after drug discontinuation, and these analgesic effects lasted until the 21st day after surgery (i.e., the 7th day after drug discontinuation) (P < 0.05). Furthermore, when icaritin was administered at a half-effective dose (1× EC50, 100 mg/kg) in combination with morphine, it reduced the required morphine dosage by up to 60% while maintaining the best analgesic effect achievable with morphine. Conclusion: Icaritin exhibits a significant analgesic effect on bone cancer pain in mice. When combined with morphine, icaritin not only prolongs post-analgesic effects after drug discontinuation but also reduces the required morphine dosage by up to 60%.