The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception
Sarton, E.; Teppema, L.J.; Olievier, C.; Nieuwenhuijs, D.; Matthes, H.W.; Kieffer, B.L.; Dahan, A.
Anesthesia and Analgesia 93(6): 1495-500 Table of Contents
2001
ISSN/ISBN: 0003-2999 PMID: 11726430 Document Number: 535826
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 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 mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception.