Substitution of a mutant α(2a)-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and α(2) adrenergic receptor (α(2)AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each α(2)AR subtype (α(2A), α(2B), and α(2C)) plays in these central effects. Here we demonstrate that α(2)AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated α(2A)AR, D79N α(2A)AR, created by two-step homologous recombination. These functional changes are accompanied by failure of the D79N α(2A)AR to inhibit voltage-gated Ca(2+) currents and spontaneous neuronal firing, a measure of K(+) current activation. These results provide definitive evidence that the α(2A)AR subtype is the primary mediator of clinically important central actions of α(2)AR agonists and suggest that the D79N α(2A)AR mouse may serve as a model for exploring other possible α(2A)AR functions in vivo.