Interactions between imidazoline I₂ receptor ligands and acetaminophen in adult male rats: Antinociception and schedule-controlled responding

Rationale: Recent evidence suggests that imidazoline I₂ receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I₂ receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies. Objective: This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I₂ receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. Methods: Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. Results: 2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. Conclusions: Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I₂ receptor ligands are not well suited to combination therapy with acetaminophen.