Abstract
Agonists acting at α2-adrenergic receptors (α2ARs) produce antinociception and synergize with opioids. The α2ARs are divided into three subtypes, α2AAR, α2BAR, and α2CAR. Most α2AR agonists require α2AAR 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-α2AAR-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-α2AAR 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 α2AARs or α2CARs. 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 α2AAR. 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 α2AAR to the other α2AR subtype(s) in the absence of α2AAR. Antinociceptive synergy with deltorphin II was preserved in the absence of either α2AAR or α2CAR. In conclusion, ST91 activates both α2AAR and non-α2AAR 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.
Footnotes
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This work was supported by the National Institutes of Health Grants R21-DA-017075 (to L.S.S.), R01-DA-04274 and R01-DA-15438 (to G.L.W.), and K01-DA-00509 (to C.A.F.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.125526.
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ABBREVIATIONS: α2AR, α2-adrenergic receptor; UK-14,304, 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; prazosin, 4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone; ARC 239, 2-(2,4-(O-methoxyphenyl)-piperazin-1-yl)ethyl-4,4-dimethyl-1, 3-(2H,4H)-isoquinolindione; KO, knockout; WT, wild type; ST91, 2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride; SKF-86466, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine; BRL-44408, 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole maleate; deltorphin II, Tyr-d-Ala-Phe-Glu-Val-Val-Gly amide; idazoxan, (±)-2-[1,4-benzodioxan-2-yl]-2-imidazoline hydrochloride; SP, substance P, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2; 5-HT, 5-hydroxytryptamine; CNS, central nervous system; CI, confidence interval.
- Received July 31, 2007.
- Accepted September 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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