Sarton E, Teppema L J, Olievier C, Nieuwenhuijs D, Matthes H W, Kieffer B L, Dahan A
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Anesth Analg. 2001 Dec;93(6):1495-500, table of contents. doi: 10.1097/00000539-200112000-00031.
N-methyl-D-aspartate receptor antagonism probably accounts for most of ketamine's anesthetic effects; its analgesic properties are mediated partly via N-methyl-D-aspartate and partly via opioid receptors. We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO(2) was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR(-/-) mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% +/- 15% and 49% +/- 6% in WT and MOR(-/-) mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR(-/-) mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR(-/-) mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception.
The involvement of the mu-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the mu-opioid receptor and in mice with intact mu-opioid receptors.
N-甲基-D-天冬氨酸受体拮抗作用可能是氯胺酮大部分麻醉作用的原因；其镇痛特性部分通过N-甲基-D-天冬氨酸受体介导，部分通过阿片受体介导。我们通过在外显子2μ-阿片受体基因敲除小鼠（MOR(-/-)）及其野生型同窝小鼠（WT）中进行剂量反应曲线，评估了μ-阿片受体在S(+)氯胺酮诱导的呼吸抑制和抗伤害感受中的作用。用全身体积描记法测量对吸入CO(2)增加的通气反应。使用了两种抗伤害感受试验：尾浸试验和热板试验。S(+)氯胺酮（0、10、100和200mg/kg腹腔注射）在两种基因型中均引起剂量依赖性呼吸抑制，与MOR(-/-)小鼠相比，WT小鼠的抑制作用更强。在200mg/kg时，S(+)氯胺酮使WT和MOR(-/-)小鼠的高碳酸通气反应斜率分别降低93%±15%和49%±6%（P<0.001）。在两种基因型中，S(+)氯胺酮在热板试验中均使潜伏期呈剂量依赖性增加，与WT动物相比，MOR(-/-)小鼠的潜伏期更短（P<0.05）。与WT小鼠相反，MOR(-/-)小鼠在尾浸试验中未表现出氯胺酮诱导的抗伤害感受。这些结果表明，在脊髓上部位，S(+)氯胺酮与μ-阿片系统相互作用。这种相互作用对S(+)氯胺酮诱导的呼吸抑制和脊髓上抗伤害感受有显著贡献。
通过在缺乏μ-阿片受体的小鼠和具有完整μ-阿片受体的小鼠中进行实验，证明了μ-阿片受体系统参与S(+)氯胺酮诱导的呼吸抑制以及脊髓和脊髓上镇痛。
