ASSESSMENT OF THE ROLE OF ALPHA(2)-ADRENOCEPTOR SUBTYPES IN THE ANTINOCICEPTIVE, SEDATIVE AND HYPOTHERMIC ACTION OF DEXMEDETOMIDINE IN TRANSGENIC MICE

1 The role of alpha(2)-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been inv estigated by determining the activity of the alpha(2)AR selective agon ist dexmedetomidine (Dex) in mice devoid of individual alpha(2)AR subt ypes through either a point (alpha(2A)) Or null (alpha(2B)/alpha(2C)) mutation ('knock-out'). 2 In a rodent model of acute thermal nocicepti on, the mouse tail immersion test, Dex, in wild type (WT) control anim als, produced a dose-dependent increase in the threshold for tail with drawal 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 m u g kg(-1), i.p.), was completely ineffective as an antinociceptive ag ent 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 produc ed 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.) produ ced a dose-dependent reduction in spontaneous locomotor activity in th e alpha(2A), alpha(2B) and alpha(2C)AR WT control animals with ED50 va lues of 30.1+/-9.0, 23.5+/-7.1 and 32.3+/-4.6 mu g kg(-1), i.p., respe ctively. Again, Dex (100-1000 mu g kg(-1), i.p.) was ineffective at mo dulating 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 r eduction 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-depend ent reduction in body temperature in the alpha(2A), alpha(2B) and alph a(2C)AR WT control mice with ED50 values of 60.6+/-11.0, 16.2+/-2.5 an d 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 pr oduced a significant reduction (-6.2+/-0.5 degrees C; P<0.01 vs vehicl e) 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 degre es C (both P<0.01 vs vehicle), respectively. In the alpha(2B)AR and al pha(2C)AR knock-out mice, Dex produced a dose-dependent reduction in b ody 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 pre dominant subtype involved in the mediation of the antinociceptive, sed ative and hypothermic actions of Dex. This profile would appear to ind icate that an alpha(2A)AR subtype selective analgesic will have a narr ow therapeutic window, particularly following systemic administration.