Antinociceptive Synergism of MD-354 and Clonidine. Part II. The alpha(2)-Adrenoceptor Component

作者：Young Shawquia; Vainio Minna; Scheinin Mika; Dukat Malgorzata^*

来源：Basic and Clinical Pharmacology and Toxicology, 2010, 107(2): 690-697.

DOI：10.1111/j.1742-7843.2010.00563.x

Previously, we reported that antinociceptive synergism of a 5-HT3/alpha(2)-adrenoceptor ligand MD-354 (m-chlorophenylguanidine) and clonidine combination occurs, in part, through a 5-HT3 receptor antagonist mechanism. In the present investigation, a possible role for alpha(2)-adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a preferential alpha(2A)-adrenoceptor antagonist) and imiloxan (a preferential alpha(2B/C)-adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD(50) = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl-3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to alpha(2A)- and alpha(2B)-adrenoceptors (K-i = 110 and 220 nM) and showed lower affinity at alpha(2C)-adrenoceptors (K-i = 4,700 nM). MD-354 had no subtype-selectivity for the alpha(2)-adrenoceptor subtypes as an antagonist in functional [35S]GTP gamma S binding assays. MD-354 was a weak partial agonist at alpha(2A)-adrenoceptors. Overall, in addition to the 5-HT3 receptor component, the present investigation found MD-354 to be a weak partial alpha(2A)-adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an alpha(2)-adrenoceptor-mediated mechanism without augmenting sedation.

• 出版日期2010-8