Assessment of the role of α 2 ‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

1 The role of α 2 ‐adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the α 2 AR selective agonist dexmedetomidine (Dex) in mice devoid of individual α 2 AR subtypes through either a point (α 2A ) or null (α 2B /α 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 ED 50 values of 99.9±14.5 (α 2A ), 94.6±17.8 (α 2B ) and 116.0±17.1 (α 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 α 2A AR D79N mutant animals. Conversely, in the α 2B AR and α 2C AR knock‐outs, Dex produced a dose‐dependent antinociceptive effect that was not significantly different from that observed in WT controls, with ED 50 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 α 2A , α 2B and α 2C AR WT control animals with ED 50 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 α 2A AR D79N mutants. In the α 2B AR and α 2C AR knock‐out mice, Dex produced a dose‐dependent reduction in spontaneous locomotor activity with ED 50 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 α 2A , α 2B and α 2C AR WT control mice with ED 50 values of 60.6±11.0, 16.2±2.5 and 47.2±9.1 μg kg −1 , i.p., respectively. In the α 2A AR 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 α 2B AR and α 2C AR knock‐out mice, Dex produced a dose‐dependent reduction in body temperature with ED 50 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 α 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 α 2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.