Tsujita Miki, Sakuraba Shigeki, Kuribayashi Junya, Hosokawa Yuki, Hatori Eiki, Okada Yasumasa, Kashiwagi Masanori, Takeda Junzo, Kuwana Shun-Ichi
Department of Anesthesiology, School of Medicine, Keio University, Tokyo, Japan.
Biol Res. 2007;40(3):339-46. Epub 2008 Apr 17.
Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.
吗啡常用于癌症疼痛和术后镇痛管理，但会诱发呼吸抑制。因此，人们一直在寻找能够拮抗吗啡诱发的呼吸抑制但对吗啡诱导的镇痛无影响的候选药物。乙酰胆碱是中枢呼吸控制中的一种兴奋性神经递质，毒扁豆碱可拮抗吗啡诱发的呼吸抑制。然而，毒扁豆碱尚未应用于临床实践，因为它具有作用时间短等特点。因此，我们研究了多奈哌齐（一种用于治疗阿尔茨海默病的长效乙酰胆碱酯酶抑制剂）是否能拮抗吗啡诱发的呼吸抑制。以麻醉兔为模型，我们测量膈神经放电作为呼吸频率和幅度的指标。我们将对照指标与注射吗啡后及注射多奈哌齐后的放电情况进行了比较。多奈哌齐部分拮抗了吗啡诱发的呼吸频率和呼吸幅度抑制，且对血压和呼气末二氧化碳无影响。在另一项实验中，我们还比较了呼吸暂停阈值PaCO₂。吗啡增加了膈神经呼吸暂停阈值，但这被多奈哌齐所拮抗。这些发现表明，全身给予多奈哌齐可部分恢复麻醉兔中吗啡诱发的呼吸抑制以及吗啡恶化的膈神经呼吸暂停阈值。
