Fig. 5. Clonidine (Clon)– and dexmedetomidine (Dex)–induced sedation/motor impairment. Rotarod performance was challenged by intrathecally (i.t.) administered clonidine, dexmedetomidine, or both in Institute of Cancer Research (ICR) ( A ), α2A-adrenergic receptor (AR) wild-type (WT) ( B ), α2CAR-WT ( C ), α2AAR-D79N ( D ), and α2CAR knockout (KO) mice ( E ). Neither clonidine (•), dexmedetomidine (▪), nor the 1:1 combination (□) exhibited greater than 40% efficacy up to the highest doses used in the substance P test. The combination did, however, result in the production of this modest efficacy at lower doses, representing significant potentiation. ( B ) In α2AAR-WT mice, clonidine exhibited full efficacy at 10 nmol (•), whereas the maximum efficacy of dexmedetomidine at that dose fell short of 50% (▪). The 1:1 combination (□) dose–response curve shifted significantly to the left (approximately 10-fold) relative to clonidine alone with comparable efficacy, and the interaction was found to be synergistic (isobologram not shown; P < 0.05, t test). ( C ) In α2CAR-WT mice, both clonidine and dexmedetomidine inhibited rotarod performance with full efficacy. The 1:1 combination (□) dose–response curve shifted significantly to the left (approximately 100-fold) relative to either drug alone with comparable efficacy, and the interaction was found to be synergistic (isobologram not shown; P < 0.05, t test). ( D ) In α2AAR-D79N mice, neither clonidine (•), dexmedetomidine (▪), nor the 1:1 combination (⋄) reduced rotarod performance more than 30%. ( E ) In α2CAR-KO mice, neither clonidine (•), dexmedetomidine (▪), nor the 1:1 combination (□) reduced rotarod performance more than 50%. Group sizes were five mice per group.