Premium
Antinociceptive Synergism of MD‐354 and Clonidine. Part II. The α 2 ‐Adrenoceptor Component
Author(s) -
Young Shawquia,
Vainio Minna,
Scheinin Mika,
Dukat Małgorzata
Publication year - 2010
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2010.00563.x
Subject(s) - clonidine , yohimbine , antagonist , agonist , chemistry , pharmacology , partial agonist , nociception , adrenergic receptor , imidazoline receptor , receptor , endocrinology , medicine , biochemistry
Previously, we reported that antinociceptive synergism of a 5‐HT 3 /α 2 ‐adrenoceptor ligand MD‐354 ( m ‐chlorophenylguanidine) and clonidine combination occurs, in part, through a 5‐HT 3 receptor antagonist mechanism. In the present investigation, a possible role for α 2 ‐adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non‐selective α 2 ‐adrenoceptor antagonist), BRL 44408 (a preferential α 2A ‐adrenoceptor antagonist) and imiloxan (a preferential α 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‐ 3 H]RS‐79948‐197 was used as radioligand, MD‐354 displayed almost equal affinity to α 2A ‐ and α 2B ‐adrenoceptors ( K i = 110 and 220 nM) and showed lower affinity at α 2C ‐adrenoceptors ( K i = 4,700 nM). MD‐354 had no subtype‐selectivity for the α 2 ‐adrenoceptor subtypes as an antagonist in functional [ 35 S]GTPγS binding assays. MD‐354 was a weak partial agonist at α 2A ‐adrenoceptors. Overall, in addition to the 5‐HT 3 receptor component, the present investigation found MD‐354 to be a weak partial α 2A ‐adrenoceptor agonist that enhances clonidine’s thermal antinociceptive actions through an α 2 ‐adrenoceptor‐mediated mechanism without augmenting sedation.