title: Morphine-induced antinociception in the rat: supra-additive interactions with imidazoline I₂ receptor ligands.
abstract: Pain remains a significant clinical challenge and currently available analgesics are not adequate to meet clinical needs. Emerging evidence suggests the role of imidazoline I(2) receptors in pain modulation primarily from studies of the non-selective imidazoline receptor ligand, agmatine. However, little is known of the generality of the effect to selective I(2) receptor ligands. This study examined the antinociceptive effects of two selective I(2) receptor ligands 2-BFI and BU224 (>2000-fold selectivity for I(2) receptors over α(2) adrenoceptors) in a hypertonic (5%) saline-induced writhing test and analyzed their interaction with morphine using a dose-addition analysis. Morphine, 2-BFI and BU224 but not agmatine produced a dose-dependent antinociceptive effect. Both composite additive curve analyses and isobolographical plots revealed a supra-additive interaction between morphine and 2-BFI or BU224, whereas the interaction between 2-BFI and BU224 was additive. The antinociceptive effect of 2-BFI and BU224 was attenuated by the I(2) receptor antagonist/α(2) adrenoceptor antagonist idazoxan but not by the selective α(2) adrenoceptor antagonist yohimbine, suggesting an I(2) receptor-mediated mechanism. Agmatine enhanced the antinociceptive effect of morphine, 2-BFI and BU224 and the enhancement was prevented by yohimbine, suggesting that the effect was mediated by α(2) adrenoceptors. Taken together, these data represent the first report that selective I(2) receptor ligands have substantial antinociceptive activity and produce antinociceptive synergy with opioids in a rat model of acute pain. These data suggest that drugs acting on imidazoline I(2) receptors may be useful either alone or in combination with opioids for the treatment of pain.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, NY 14214, USA. junxuli@buffalo.edu
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jerrold C
authors.initials: JC
authors.lastname: Winter
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000376:Agmatine / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000378:metabolism*; D008024:Ligands; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D000701:Analgesics, Opioid; C105826:BU 224; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D012462:Saline Solution, Hypertonic; C487767:imidazoline receptor 2; D015016:Yohimbine; D000376:Agmatine; C103723:2-(2-benzofuranyl)-2-imidazoline; D009020:Morphine; D019329:Idazoxan