Voss Logan J, Harvey Martyn G, Sleigh James W
Anaesthesia Department, Waikato District Health Board, Hamilton, New Zealand.
Emergency Department, Waikato District Health Board, Hamilton, New Zealand.
Front Pain Res (Lausanne). 2022 Feb 15;3:827372. doi: 10.3389/fpain.2022.827372. eCollection 2022.
Despite 50 years of clinical use and experimental endeavor the anesthetic, analgesic, and psychomimetic effects of ketamine remain to be fully elucidated. While NMDA receptor antagonism has been long held as ketamine's fundamental molecular action, interrogation of bespoke ketamine analogs with known absent NMDA binding, yet profound anesthetic and analgesia fingerprints, suggests alternative targets are responsible for these effects. Herein we describe experimental findings utilizing such analogs as probes to explore ketamine-based analgesic molecular targets. We have focused on two-pore potassium leak channels, identifying TWIK channels as a rational target to pursue further. While the totality of ketamine's mechanistic action is yet to be fully determined, these investigations raise the intriguing prospect of separating out analgesia and anesthetic effects from ketamine's undesirable psychomimesis-and development of more specific analgesic medications.
尽管氯胺酮已临床应用50年且经过了大量实验研究，但其麻醉、镇痛和拟精神病效应仍有待充分阐明。虽然长期以来人们一直认为NMDA受体拮抗作用是氯胺酮的基本分子作用，但对已知缺乏NMDA结合但具有显著麻醉和镇痛特征的定制氯胺酮类似物进行研究后发现，可能存在其他靶点导致这些效应。在此，我们描述了利用此类类似物作为探针来探索基于氯胺酮的镇痛分子靶点的实验结果。我们聚焦于双孔钾离子渗漏通道，确定TWIK通道是值得进一步研究的合理靶点。虽然氯胺酮的作用机制尚未完全确定，但这些研究提出了一个有趣的前景，即有可能将氯胺酮的镇痛和麻醉作用与不良的拟精神病作用分离，并开发出更具特异性的镇痛药物。
