Anesthesia and analgesia
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Anesthesia and analgesia · Dec 2001
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. ⋯ 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.
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Anesthesia and analgesia · Dec 2001
Cariporide (HOE 642) attenuates leukocyte activation in ischemia and reperfusion.
Cariporide (HOE 642) ameliorates myocardial ischemia/reperfusion (I/R) injury, by the well established reduction of cytosolic [Ca(2+)] in cardiac myocytes through inhibition of Na(+)/H(+) exchange. However, postischemic inflammation also contributes to I/R injury. We tested the hypothesis that cariporide also modulates the inflammatory response. The effect of cariporide on L-selectin expression by human leukocytes in vitro and leukocyte adhesion and emigration in the reperfused rat cremaster muscle in vivo were studied. The rat cremaster muscle was exteriorized for intravital videomicroscopy, induction of ischemia (90 min), and reperfusion (90 min). Eleven rats were pretreated with cariporide (9 mg/kg body weight IV) whereas 11 rats received saline. Leukocyte adhesion was quantified offline. Human venous blood was incubated with cariporide (3 micromol/L) or saline, stimulated with formyl- methionine-leucine-phenylalanine (10(-10)-10(-6) mol/L), and granulocyte L-selectin expression was analyzed by flow cytometry. Cariporide reduced leukocyte rolling and adhesion by approximately 35% and 45%, respectively, after 30 min of reperfusion. Leukocyte extravasation was decreased by approximately 85% after 90 min. Cariporide increased L-selectin shedding at each formyl-methionine-leucine-phenylalanine concentration, reducing the 50% effective dose from 9.95 to 4.68 nmol/L. Thus, cariporide may ameliorate I/R injury not only by the known reduction of cytosolic [Ca(2+)] in cardiomyocytes, but also by attenuating leukocyte-dependent inflammatory responses. Promotion of L-selectin shedding from activated leukocytes may present a mechanism underlying this newly detected effect. ⋯ This study provides evidence that inhibition of Na(+)/H(+) exchange by cariporide (HOE 642) attenuates the postischemic inflammatory response. Leukocyte adhesion and emigration, assessed by in vivo microscopy, were markedly reduced in rat cremaster muscle, possibly because of increased L-selectin shedding of activated leukocytes as demonstrated by flow cytometry.