Participation of ATP-sensitive K+ channels and μ-opioid receptors in the antinociceptive synergism of the paracetamol– tapentadol co-administration in the formalin-induced pain assay in mice

Abstract

The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol‐tapentadol combination in the formalin‐induced pain model in mice. Paracetamol (56.23–562.3 mg/kg, i.p.) or tapentadol (1–10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose–response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1). Naloxone (1 and 5 mg/kg, i.p.), L‐NAME (3 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.) were administered before the combination of drugs to evaluate the antinociceptive mechanisms of action. The results showed that the combination 1:1 and paracetamol3‐tapenadol1 ratios produced additive effects, whereas the paracetamol1‐tapentadol3 proportion showed an antinociceptive synergistic interaction. Moreover, naloxone and glibenclamide reversed the antinociceptive activity of the paracetamol‐tapentadol mixture. Our results indicate that the paracetamol‐tapentadol combination produces an antinociceptive synergistic interaction with the possible participation of ATP‐sensitive K+ channels and μ‐opioid receptors in the second phase of the formalin‐induced pain model in mice.