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Pain remains a significant clinical challenge and currently available analgesics are not adequate to meet clinical needs. Emerging evidence suggests the role of imidazoline I2 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 I2 receptor ligands. This study examined the antinociceptive effects of two selective I2 receptor ligands 2-BFI and BU224 (> 2000-fold selectivity for I2 receptors over α2 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 I2 receptor antagonist/α2 adrenoceptor antagonist idazoxan but not by the selective α2 adrenoceptor antagonist yohimbine, suggesting an I2 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 α2 adrenoceptors. Taken together, these data represent the first report that selective I2 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 I2 receptors may be useful either alone or in combination with opioids for the treatment of pain.