ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride]-mediated spinal antinociception and synergy with opioids persists in the absence of functional α-2A- or α-2C-adrenergic receptors

Agonists acting at α₂-adrenergic receptors (α₂ARs) produce antinociception and synergize with opioids. The α₂ARs are divided into three subtypes, α_2AAR, α_2BAR, and α_2CAR. Most α₂AR agonists require α_2AAR activation to produce antinociception and opioid synergy. The same subtype also mediates the side effect of sedation, which limits the clinical utility of these compounds. Identification of a non-α_2AAR-mediated antinociceptive agent would enhance the therapeutic utility of α₂AR agonists in pain management. Previous studies have suggested that the α₂AR agonist ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride] has a nonsedating, non-α_2AAR mechanism of action. We examined the pharmacology of spinal ST91 and its interaction with the δ-opioid agonist deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide) in mice lacking either functional α_2AARs or α_2CARs. All drugs were administered by direct lumbar puncture, and drug interactions were evaluated using isobolographic analysis. In contrast to the majority of α₂AR agonists, ST91 potency was only moderately reduced (3-fold) in the absence of the α_2AAR. Studies with the α₂AR subtype-preferring antagonists BRL-44408 (2-[2H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole maleate) and prazosin [[4-(4-amino-6,7-dimethoxy- quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone] and the pan-α₂AR antagonist SKF-86466 (6-chloro-2,3,4,5-tetrahydro-3- methyl-1-H-3-benzazepine) suggest a shift from α_2AAR to the other α₂AR subtype(s) in the absence of α_2AAR. Antinociceptive synergy with deltorphin II was preserved in the absence of either α_2AAR or α_2CAR. In conclusion, ST91 activates both α_2AAR and non-α_2AAR subtypes to produce spinal antinociception and opioid synergy. This study confirms that the spinal pharmacology of ST91 differs from that of other α₂AR agonists and extends those data to include spinal synergy with opioid agonists. The unique profile of ST91 may be advantageous in pain management.