Morphine-induced antinociception in the rat: Supra-additive interactions with imidazoline I ₂ receptor ligands

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.