Naloxone Reverses the Antinociceptive Synergistic Interaction Between Acetaminophen and Lysine Clonixinate in the Formalin Test

Abstract

Preclinical Research The purpose of this study was to evaluate the antinociceptive interaction between acetaminophen and lysine clonixinate in the formalin test, and the possible role of opioidergic and nitric oxide pathways in the interaction. The effect of individual drugs and their combination was evaluated using the 3% formalin test in mice. Acetaminophen (31.6, 100, 178, and 316 mg/kg, i.p.) or lysine clonixinate (5.6, 10, 17.8, and 31.6 mg/kg, i.p.) were administered 10 min before formalin injection. To assess the possible mechanism(s) of action for the combination, naloxone (1 mg/kg) and N (G)‐nitro‐L‐arginine methyl ester (L‐NAME) (3 mg/kg) were used. Isobolographic analysis and the interaction index showed a synergistic effect. The experimental ED30 was lower when compared with theoretical ED30. Naloxone, but not L‐NAME, reduced the antinociceptive effect of the combination. Administration of antagonists alone did not modify formalin‐induced nociception. These data suggest that the acetaminophen–lysine clonixinate combination produces a synergistic effect involving opioid receptors.

Involvement of Nitric Oxide and ATP‐Sensitive Potassium Channels in the Peripheral Antinoceptive Action of a Tramadol–Dexketoprofen Combination in the Formalin Test

“…In our study, the maximal antinociceptive effect was 74%, which was obtained with 178 μg/30 μL (paw). The lack of antinociceptive activity of local dexketoprofen in the first phase of the formalin test was consistent with previous studies [Kolesnikov et al., ; Zelcer et al., ; Isiordia‐Espinoza et al., , ].…”

“…Isobolographic analysis and interaction index were used as previously described [Tallarida, 2000;Isiordia-Espinoza et al, 2013]. The theoretical additive ED 50 and the experimentally derived ED 50 values were evaluated using Student's t-test.…”