Anti-hyperalgesic effects of imidazoline I₂ receptor ligands in a rat model of inflammatory pain: Interactions with oxycodone

Rationale: Emerging preclinical evidence suggests that imidazoline I₂ receptor ligands may be effective analgesics. Quantitative analysis of the combined I₂ receptor ligands and opioids is needed for the justification of combination therapy. Objective: This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I₂ receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats. Methods: Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs. Results: Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.), and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations. Conclusions: Quantitative analysis of the anti-hyperalgesic effects of I₂ receptor ligands strongly supports the therapeutic potential of I₂ receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I₂ receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.