The imidazoline I₂ receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination

Rationale: Increasing evidence shows that imidazoline I₂ receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I₂ receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I₂ receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I₂ receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. Objectives: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I₂ receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. Results: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. Conclusions: These results suggest that I₂ receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I₂ receptor agonist-opioid combination therapy for pain control.