The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception.
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.


CONCLUSIONS
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.
Sarton
E
E
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Teppema
L J
LJ
Olievier
C
C
Nieuwenhuijs
D
D
Matthes
H W
HW
Kieffer
B L
BL
Dahan
A
A
D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide / Q000502:physiology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017288:Pain Threshold / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology*; D012119:Respiration / Q000187:drug effects*
D000700:Analgesics; D017450:Receptors, Opioid, mu; D002245:Carbon Dioxide; D007649:Ketamine