title: Effects of imidazoline I₂ receptor ligands on morphine- and tramadol-induced antinociception in rats.
abstract: Currently available analgesics cannot meet the increasing clinical needs and new analgesics with better therapeutic profiles are in great demand. The imidazoline I₂ receptor is an emerging drug target for analgesics. However, few studies have examined the effects of selective I₂ receptor ligands on the antinociceptive activity of opioids. This study examined the antinociceptive effects of the opioids morphine (0.1-10 mg/kg) and tramadol (3.2-56 mg/kg), the nonselective I₂ receptor ligand agmatine (10-100 mg/kg), and the selective I₂ receptor ligands 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI; 1-10 mg/kg) and 2-(4, 5-dihydroimidazol-2-yl) quinoline hydrochloride (BU224; 1-10mg/kg), alone and in combination, in a warm water tail withdrawal procedure in rats. Morphine and tramadol but not agmatine, 2-BFI or BU224 increased tail withdrawal latency in a dose-related manner at 48°C water. Agmatine and 2-BFI but not BU224 dose-dependently enhanced the antinociceptive effects of morphine and tramadol, shifting the dose-effect curves of morphine and tramadol leftward. The enhancement of agmatine and 2-BFI on morphine and tramadol antinociception was prevented by BU224. These results, combined with the fact that BU224 and 2-BFI share similar behavioral effects under other conditions, suggest that BU224 has lower efficacy than 2-BFI at I₂ receptors, and that the enhancement of opioid antinociception by I₂ receptor ligands depends on their efficacies.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, NY 14214, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Thorn
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bi-Wen
authors.initials: BW
authors.lastname: Peng
authors.forename: Jerrold C
authors.initials: JC
authors.lastname: Winter
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000376:Agmatine / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000378:metabolism*; D008024:Ligands; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014147:Tramadol / Q000494:pharmacology*
chemical_list: D000700:Analgesics; C105826:BU 224; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; C487767:imidazoline receptor 2; D014147:Tramadol; D000376:Agmatine; C103723:2-(2-benzofuranyl)-2-imidazoline; D009020:Morphine