1 The role of alpha(2)-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the alpha(2)AR selective agonist dexmedetomidine (Dex) in mice devoid of individual alpha(2)AR subtypes through either a point (alpha(2A)) Or null (alpha(2B)/alpha(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 degrees C water bath with mean ED50 values of 99.9+/-14.5 (alpha(2A)), 94.6+/-17.8 (alpha(2B)) and 116.0+/-17.1 (alpha(2C)) mu g kg(-1), i.p. 3 In comparison to the WT controls, Dex (100-1000 mu g kg(-1), i.p.), was completely ineffective as an antinociceptive agent in the tail immersion test in the alpha(2A)AR D79N mutant animals. Conversely, in the alpha(2B)AR and alpha(2C)AR 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) mu g kg(-1) i.p., respectively. 4 Dex (10-300 mu g kg(-1), i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the alpha(2A), alpha(2B) and alpha(2C)AR WT control animals with ED50 values of 30.1+/-9.0, 23.5+/-7.1 and 32.3+/-4.6 mu g kg(-1), i.p., respectively. Again, Dex (100-1000 mu g kg(-1), i.p.) was ineffective at modulating motor behaviour in the alpha(2A)AR D79N mutants. In the alpha(2B)AR and alpha(2C)AR 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) mu g kg(-1), respectively. 5 Dex was also found to produce a dose-dependent reduction in body temperature in the alpha(2A), alpha(2B) and alpha(2C)AR WT control mice with ED50 values of 60.6+/-11.0, 16.2+/-2.5 and 47.2+/-9.1 mu g kg(-1), i.p., respectively. In the alpha(2A)AR D79N mutants, Dex had no effect on body temperature at a dose i.p.) that produced a significant reduction (-6.2+/-0.5 degrees C; P<0.01 vs vehicle) in WT controls. However, higher doses of Dex (300 and 1000 mu g kg(-1), i.p) produced a small, but statistically significant decrease in temperature corresponding to -1.7+/-0.4 degrees C and -2.4+/-0.3 degrees C (both P<0.01 vs vehicle), respectively. In the alpha(2B)AR and alpha(2C)AR 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) mu g kg(-1), respectively. 6 In conclusion, the data are consistent with the alpha(2A)AR 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 alpha(2A)AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.
