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 α₂ adrenergic receptor (α₂AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each α₂AR subtype (α_2A, α_2B, and α_2C) plays in these central effects. Here we demonstrate that α₂AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated α_2AAR, D79N α_2AAR, created by two-step homologous recombination. These functional changes are accompanied by failure of the D79N α_2AAR to inhibit voltage-gated Ca²⁺ currents and spontaneous neuronal firing, a measure of K⁺ current activation. These results provide definitive evidence that the α_2AAR subtype is the primary mediator of clinically important central actions of α₂AR agonists and suggest that the D79N α_2AAR mouse may serve as a model for exploring other possible α_2AAR functions in vivo.