Effects of imidazoline I ₂ receptor agonists and morphine on schedule-controlled responding in rats

Accumulating evidence indicates that imidazoline I ₂ receptor agonists enhance the antinociceptive effects of opioids and therefore may be suitable for combination therapy with opioids for pain treatment. However, little is known of the effects of I ₂ receptor agonists on other behavioral effects of opioids. This study used schedule-controlled responding and dose-addition analyses to examine interactions between the μ opioid receptor agonist morphine and two imidazoline I ₂ receptor agonists, 2-BFI and BU224. In 8 rats responding under a fixed ratio 10 schedule of food presentation, morphine (3.2-17.8 mg/kg), 2-BFI (3.2-17.8 mg/kg), and BU224 (5.6-17.8 mg/kg) each dose-dependently decreased responding. The addition of fixed proportions of 2-BFI or BU224 shifted the morphine dose-effect curves leftward. The interactions between morphine and 2-BFI or BU224 were infra-additive when the same proportions of morphine and I ₂ receptor agonists were mixed; however, the interaction between morphine and I ₂ receptor agonists was additive when the drugs were mixed at other proportions. These results provide quantitative evidence that I ₂ receptor agonists do not enhance the response rate-decreasing effect of morphine and suggest that the enhancement of morphine antinociception is selective. Together, these results further support the therapeutic potential of combining I ₂ receptor agonists and opioids for pain control.