Effects of imidazoline I2 receptor agonists and morphine on schedule-controlled responding in rats

Accumulating evidence indicates that imidazoline I2 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 I2 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 I2 receptor agonists, 2-BFI and BU224. In 8 rats responding under a fixed ratio 10 schedule of food presentation, morphine (3.2–17.8mg/kg), 2-BFI (3.2–17.8mg/kg), and BU224 (5.6–17.8mg/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 I2 receptor agonists were mixed; however, the interaction between morphine and I2 receptor agonists was additive when the drugs were mixed at other proportions. These results provide quantitative evidence that I2 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 I2 receptor agonists and opioids for pain control.