ST91 [2-(2,6-Diethylphenylamino)-2-imidazoline Hydrochloride]-Mediated Spinal Antinociception and Synergy with Opioids Persists in the Absence of Functional {alpha}-2A- or {alpha}-2C-Adrenergic Receptors.

Agonists acting at alpha(2)-adrenergic receptors (alpha(2)ARs) produce antinociception and synergize with opioids. The alpha(2)ARs are divided into three subtypes, alpha(2A)AR, alpha(2B)AR, and alpha(2C)AR. Most alpha(2)AR agonists require alpha(2A)AR 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-alpha(2A)AR-mediated antinociceptive agent would enhance the therapeutic utility of alpha(2)AR agonists in pain management. Previous studies have suggested that the alpha(2)AR agonist ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride] has a nonsedating, non-alpha(2A)AR mechanism of action. We examined the pharmacology of spinal ST91 and its interaction with the delta-opioid agonist deltorphin II (Tyr-d-Ala-Phe-Glu-Val-Val-Gly amide) in mice lacking either functional alpha(2A)ARs or alpha(2C)ARs. All drugs were administered by direct lumbar puncture, and drug interactions were evaluated using isobolographic analysis. In contrast to the majority of alpha(2)AR agonists, ST91 potency was only moderately reduced (3-fold) in the absence of the alpha(2A)AR. Studies with the alpha(2)AR 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-alpha(2)AR antagonist SKF-86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine) suggest a shift from alpha(2A)AR to the other alpha(2)AR subtype(s) in the absence of alpha(2A)AR. Antinociceptive synergy with deltorphin II was preserved in the absence of either alpha(2A)AR or alpha(2C)AR. In conclusion, ST91 activates both alpha(2A)AR and non-alpha(2A)AR subtypes to produce spinal antinociception and opioid synergy. This study confirms that the spinal pharmacology of ST91 differs from that of other alpha(2)AR agonists and extends those data to include spinal synergy with opioid agonists. The unique profile of ST91 may be advantageous in pain management.