Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands.
Neurosci Lett. 2019 Apr 23;699:41-46. doi: 10.1016/j.neulet.2019.01.026. Epub 2019 Jan 16.
The xylazine/ketamine anesthesia test is widely used as a predictor of the emetic potential of pharmacological compounds in rats. An emetic reflex is usually triggered by the emetic center, which is populated with many different chemoreceptors. Inhibition of the α2 adrenergic receptor (α2 receptor) is involved in the initiation of the emetic reflex, and this is the key mechanism behind the xylazine/ketamine anesthesia test. In this study, we attempt to validate this test as a predictor of the emetic potential of pharmacological compounds. Furthermore, it was investigated whether an anti-emetic potential of pharmacological compounds could be assessed within this test as well. Rats were anesthetized with a combination of low doses of ketamine and xylazine, and subsequently treated with PDE4 inhibitor rolipram, α2 receptor antagonist yohimbine, α2 receptor agonist clonidine, tricyclic antidepressant imipramine, D2-receptor antagonist haloperidol, or 5-HT3 receptor antagonist (and anti-emetic drug) ondansetron. We were able to successfully reproduce the reduction in anesthesia time after rolipram or yohimbine treatment, as found in previous studies and has been suggested to be indicative of emetic properties of these treatments is humans. Furthermore, clonidine shortened anesthesia duration whereas imipramine and haloperidol lengthened anesthesia duration. Ondansetron was unable to rescue the reduction in duration of anesthesia induced by either rolipram or yohimbine. Altogether, the xylazine/ketamine anesthesia test is a reliable measure for α2 receptor antagonism. However, it may not be appropriate to assess emesis independent of this mechanism.
氯胺酮/水合氯醛麻醉试验被广泛用于预测药理学化合物在大鼠中的呕吐潜力。呕吐反射通常由呕吐中枢触发，呕吐中枢内存在许多不同的化学感受器。α2 肾上腺素能受体（α2 受体）的抑制参与了呕吐反射的启动，这是氯胺酮/水合氯醛麻醉试验的关键机制。在这项研究中，我们试图验证该试验作为预测药理学化合物呕吐潜力的指标。此外，还研究了是否可以在该试验中评估药理学化合物的止吐潜力。大鼠用低剂量的氯胺酮和水合氯醛组合麻醉，然后用 PDE4 抑制剂罗利普兰、α2 受体拮抗剂育亨宾、α2 受体激动剂可乐定、三环抗抑郁药丙咪嗪、D2 受体拮抗剂氟哌啶醇或 5-HT3 受体拮抗剂（和止吐药）昂丹司琼进行治疗。我们成功地复制了罗利普兰或育亨宾治疗后麻醉时间减少的现象，这与之前的研究结果一致，并表明这些治疗在人类中具有呕吐作用。此外，可乐定缩短了麻醉持续时间，而丙咪嗪和氟哌啶醇延长了麻醉持续时间。昂丹司琼无法挽救罗利普兰或育亨宾诱导的麻醉持续时间缩短。总的来说，氯胺酮/水合氯醛麻醉试验是评估 α2 受体拮抗作用的可靠方法。然而，评估与该机制无关的呕吐可能并不合适。
