Assessment of the role of α2-adrenoceptor subtypes in the antinociceptive sedative and hypothermic action of dexmedetomidine in transgenic mice

摘要

class="enumerated" style="list-style-type:decimal">The role of α2-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the α2AR selective agonist dexmedetomidine (Dex) in mice devoid of individual α2AR subtypes through either a point (α2A) or null (α2B/α2C) mutation (‘knock-out').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 (α2A), 94.6±17.8 (α2B) and 116.0±17.1 (α2C) μg kg⁻¹, i.p.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 α2AAR D79N mutant animals. Conversely, in the α2BAR and α2CAR 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.Dex (10–300 μg kg⁻¹, i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the α2A, α2B and α_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 α_2AAR D79N mutants. In the α_2BAR and α_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.Dex was also found to produce a dose-dependent reduction in body temperature in the α_2A, α_2B and α_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 α_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 α_2BAR and α_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.In conclusion, the data are consistent with the α_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 α_2AAR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.