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

Abstract

1 The role of a 2 -adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the a 2 AR selective agonist dexmedetomidine (Dex) in mice devoid of individual a 2 AR subtypes through either a point (a 2A ) or null (a 2B /a 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 528C water bath with mean ED 50 values of 99.9+14.5 (a 2A ), 94.6+17.8 (a 2B ) and 116.0+17.1 (a 2C ) mg kg 71 , i.p. 3 In comparison to the WT controls, Dex (100 ± 1000 mg kg 71 , i.p.), was completely ine ective as an antinociceptive agent in the tail immersion test in the a 2A AR D79N mutant animals. Conversely, in the a 2B AR and a 2C AR knock-outs, Dex produced a dose-dependent antinociceptive e ect that was not signi®cantly di erent from that observed in WT controls, with ED 50 values of 85.9+15.0 (P40.05 vs WT control) and 226.0+62.7 (P40.05 vs WT control) mg kg 71 i.p., respectively. 4 Dex (10 ± 300 mg kg 71 , i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the a 2A , a 2B and a 2C AR WT control animals with ED 50 values of 30.1+9.0, 23.5+7.1 and 32.3+4.6 mg kg 71 , i.p., respectively. Again, Dex (100 ± 1000 mg kg 71 , i.p.) was ine ective at modulating motor behaviour in the a 2A AR D79N mutants. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED 50 values of 29.1+6.4 (P40.05 vs WT control) and 57.5+11.3 (P40.05 vs WT control) mg kg 71 , respectively. 5 Dex was also found to produce a dose-dependent reduction in body temperature in the a 2A , a 2B and a 2C AR WT control mice with ED 50 values of 60.6+11.0, 16.2+2.5 and 47.2+9.1 mg kg 71 , i.p., respectively. In the a 2A AR D79N mutants, Dex had no e ect on body temperature at a dose (100 mg kg 71 , i.p.) that produced a signi®cant reduction (76.2+0.58C; P50.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 mg kg 71 , i.p) produced a small, but statistically signi®cant decrease in temperature corresponding to 71.7+0.48C and 72.4+0.38C (both P50.01 vs vehicle), respectively. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED 50 values of 28.4+4.8 (P40.05 vs WT control) and 54.1+8.0 (P40.05 vs WT control) mg kg 71 , respectively. 6 In conclusion, the data are consistent with the a 2A AR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This pro®le would appear to indicate that an a 2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.

Contribution of α2 receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

“…Furthermore, we found that the anti-allodynic and the antinociceptive eects of dexmedetomidine were intact in a 2B and a 2C AR, but absent in the a 2A AR mutant mice. Our results agree with previous reports showing that the antinociceptive eect of dexmedetomidine in the hot-plate and tail-¯ick tests is mediated via an activation of a 2A AR (Lakhlani et al, 1997;Hunter et al, 1997;Stone et al, 1997) and indicate that the same receptor comes into play under both acute and persistent pain conditions.…”

“…Previous studies suggested that the a 2A subtype mediates the antinociceptive eect of a 2 AR agonists in acute models of pain (Hunter et al, 1997;Lakhlani et al, 1997;Stone et al, 1997). However, because a 2 AR expression may be altered after nerve injury (Cho et al, 1997;Fareed et al, 1997;Birder & Perl, 1999;Stone et al, 1999;Shi et al, 2000), it is possible that the action of dexmedetomidine is altered by nerve injury or that the a 2 AR receptor subtype that is responsible for its antinociceptive eect is dierent.…”

“…On general behavioural grounds, the mutant and wild-type mice cannot be distinguished. Of the studies previously published using the dierent a 2 AR mutant mice, none report compensatory changes or abnormal behaviour due to the mutation (MacMillan et al, 1996;Link et al, 1996;Hunter et al, 1997;Stone et al, 1997). In contrast to the a 2B and a 2C AR mutant mice, which lack the receptor protein due to a null mutation (Link et al, 1996), the a 2A AR mutant mice express a point (D79N) mutation in this receptor (MacMillan et al, 1996).…”

Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

“…The almost totally abolished startle reflex of WT mice after Dex 10 and especially 30 mg/kg was likely due to its sedative effect. The sedation elicited by a 2 -AR agonists is mainly mediated through activation of a 2A -AR, and has previously been shown to be attenuated, but not totally absent in mice lacking functional a 2A -AR (Hunter et al, 1997;Lakhlani et al, 1997;Lähdesmäki et al, 2003). The smallest Dex dose, 3 mg/ kg, is not, however, sedative in mice (Hunter et al, 1997), but still effectively reduced startle in WT mice.…”

Heterozygous α 2A -adrenergic receptor mice unveil unique therapeutic benefits of partial agonists

“…Gene manipulation in mice reveals which receptor subtype elicits a particular physiological or behavioral response in vivo, and has revealed the crucial role of the ␣ 2A -adrenergic receptor (␣ 2A -AR) subtype in mediating the ability of ␣ 2 -agonists to elicit hypotension (1-3), sedation (4), anesthetic sparing and analgesia (4,5), hypothermia (6,7), synergism with opiates in the antinociceptive response (5), and enhancement of working memory in mice (10). The latter finding suggests that the beneficial effects of guanfacine in working memory in primates (11) and in the enhancement of attentional focus in patients with attention deficit hyperactivity disorder (12) is attributable to ␣ 2A -AR actions.…”