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ANESTHETIC PHARMACOLOGY

The Involvement of the µ-Opioid Receptor in Ketamine-Induced Respiratory Depression and Antinociception

Elise Sarton, MD PhD^*, Luc J. Teppema, PhD^*, Cees Olievier^*, Diederik Nieuwenhuijs, MD^*, Hans W. D. Matthes, PhD, Brigitte L. Kieffer, PhD, and Albert Dahan, MD PhD^*

*Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; and UPR 9050 CNRS, ESBS Université Louis Pasteur, Parc d’Innovation, Illkirch, Strasbourg, France

Address correspondence and reprint requests to Dr. Albert Dahan, Department of Anesthesiology, Leiden University Medical Center P5-Q, PO Box 9600, 2300 RC Leiden, The Netherlands. Address e-mail to a.dahan{at}lumc.nl

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 µ-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 µ-opioid receptor knockout mice (MOR^-/-) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO₂ 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 µ-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception.

IMPLICATIONS: The involvement of the µ-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the µ-opioid receptor and in mice with intact µ-opioid receptors.

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