The involvement of the μ-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 bt-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 ti-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception.