Assessment of the role of  2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice
J.C. Hunter1,3,
D.J. Fontana1,
L.R. Hedley1,
J.R. Jasper1,
R. Lewis1,
R.E. Link2,
R. Secchi1,
J. Sutton1 & R.M. Eglen1
1Center for Biological Research, Neurobiology Unit, Roche Bioscience, 3401 Hillview Ave., Palo Alto, CA 94304
2Department of Molecular and Cellular Physiology, Stanford University, Palo Alto, CA 94305, U.S.A.
3Author for correspondence
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1 The role of 2-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the 2AR selective agonist dexmedetomidine (Dex) in mice devoid of individual 2AR subtypes through either a point (2A) or null (2B/2C) mutation (`knock-out’).
2 In a rodent model of acute thermal nociception, the mouse tail immersion test, Dex, in wild type (WT) control animals, produced a dose-dependent increase in the threshold for tail withdrawal from a 52°C water bath with mean ED50 values of 99.9±14.5 (2A), 94.6±17.8 (2B) and 116.0±17.1 (2C) µg kg-1, i.p.
3 In comparison to the WT controls, Dex (100 – 1000 µg kg-1, i.p.), was completely ineffective as an antinociceptive agent in the tail immersion test in the 2AAR D79N mutant animals. Conversely, in the 2BAR and 2CAR knock-outs, Dex produced a dose-dependent antinociceptive effect that was not significantly different from that observed in WT controls, with ED50 values of 85.9±15.0 (P>0.05 vs WT control) and 226.0±62.7 (P>0.05 vs WT control) µg kg-1 i.p., respectively.
4 Dex (10 – 300 µg kg-1, i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the 2A, 2B and 2CAR WT control animals with ED50 values of 30.1±9.0, 23.5±7.1 and 32.3±4.6 µg kg-1, i.p., respectively. Again, Dex (100 – 1000 µg kg-1, i.p.) was ineffective at modulating motor behaviour in the 2AAR D79N mutants. In the 2BAR and 2CAR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED50 values of 29.1±6.4 (P>0.05 vs WT control) and 57.5±11.3 (P>0.05 vs WT control) µg kg-1, respectively.
5 Dex was also found to produce a dose-dependent reduction in body temperature in the 2A, 2B and 2CAR WT control mice with ED50 values of 60.6±11.0, 16.2±2.5 and 47.2±9.1 µg kg-1, i.p., respectively. In the 2AAR D79N mutants, Dex had no effect on body temperature at a dose (100 µg kg-1, i.p.) that produced a significant reduction (-6.2±0.5°C; P<0.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 µg kg-1, i.p) produced a small, but statistically significant decrease in temperature corresponding to -1.7±0.4°C and -2.4±0.3°C (both P<0.01 vs vehicle), respectively. In the 2BAR and 2CAR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED50 values of 28.4±4.8 (P>0.05 vs WT control) and 54.1±8.0 (P>0.05 vs WT control) µg kg-1, respectively.
6 In conclusion, the data are consistent with the 2AAR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This profile would appear to indicate that an 2AAR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration. |
