Anti-hyperalgesic effects of imidazoline I-2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone

Emerging preclinical evidence suggests that imidazoline I-2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I-2 receptor ligands and opioids is needed for the justification of combination therapy.

This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I-2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats.

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.

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.

Quantitative analysis of the anti-hyperalgesic effects of I-2 receptor ligands strongly supports the therapeutic potential of I-2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I-2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.