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

摘要

Agonists acting at α2-adrenergic receptors (α2ARs) produce antinociception and synergize with opioids. The α2ARs are divided into three subtypes, α_(2A)AR, α_(2B)AR, and α_(2C)AR. Most α2AR agonists require α_(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-α_(2A)AR-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-diethylphe-nylamino)-2-imidazoline hydrochloride] has a nonsedating, non-α_(2A)AR mechanism of action. We examined the pharmacology of spinal ST91 and its interaction with the S-opioid agonist deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide) in mice lacking either functional α_(2A)ARs or α_(2c)ARs. 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_(2A)AR. Studies with the α2AR subtype-preferring antagonists BRL-44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihy-droimidazole maleate) and prazosin [[4-(4-amino-6,7-dime-thoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone] and the pan-α2AR antagonist SKF-86466 (6-chloro-2,3,4,5-tetrahy-dro-3-methyl-1 -H-3-benzazepine) suggest a shift from α_(2A)AR to the other α2AR subtype(s) in the absence of α_(2A)AR. Antinociceptive synergy with deltorphin II was preserved in the absence of either α_(2A)AR or α_(2C)AR. In conclusion, ST91 activates both α_(2A)AR and non-α_(2A)AR 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.