Jc. Hunter et al., ASSESSMENT OF THE ROLE OF ALPHA(2)-ADRENOCEPTOR SUBTYPES IN THE ANTINOCICEPTIVE, SEDATIVE AND HYPOTHERMIC ACTION OF DEXMEDETOMIDINE IN TRANSGENIC MICE, British Journal of Pharmacology, 122(7), 1997, pp. 1339-1344
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.