Synergistic antinociceptive effect and gastric safety of the combination of docosahexaenoic acid and indomethacin in rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2014-07, Vol.122, p.74-81
• Main Authors: Arroyo-Lira, Arlette Guadalupe, Rodríguez-Ramos, Fernando, Chávez-Piña, Aracely Evangelina
• Format: Article
• Language: English
• Subjects: Analgesic; Analgesics - administration & dosage; Analgesics - adverse effects; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Antinociceptive; Docosahexaenoic acid; Docosahexaenoic Acids - administration & dosage; Docosahexaenoic Acids - adverse effects; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Gastric injury; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Indomethacin; Indomethacin - administration & dosage; Indomethacin - adverse effects; Interaction; Pain Measurement - drug effects; Pain Measurement - methods; Rats; Rats, Wistar; Treatment Outcome
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2014.03.015

The use of analgesics is limited by the presence of significant adverse side effects. Thus, combinations of non-steroidal anti-inflammatory drugs (NSAIDs) with other antinociceptive agents are frequently used to decrease these adverse reactions. The aims of this work were to evaluate the antinociceptive interaction of the systemic administration of the combination of DHA and indomethacin through an isobolographic analysis of the theoretical and experimental antinociceptive effect and to demonstrate the gastric safety of the mixture compared with indomethacin alone. Female Wistar rats were orally administered indomethacin (1–10mg/kg), DHA (100–300mg/kg), or the DHA–indomethacin mixture at a fixed-ratio combination (1:1, 1:3, 3:1), and the antinociceptive effects of these treatments were evaluated through the formalin (1%) test. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and indomethacin. The degree of gastric injury in all of the rats was determined 1h after the formalin test. The theoretical ED30 values (Zadd) for the 1:1, 1:3, and 3:1 combinations were 73.48±8.96, 37.75±4.50, and 109.2±13.43mg/kg, p.o., respectively, and the experimental ED30 values (Zexp) were 43.63±5.18, 13.13±1.61, and 54.20±6.53, respectively. The isobolographic analysis showed that the three fixed-ratio combinations studied exhibited a synergistic interaction. Furthermore, the gastric damage induced by indomethacin was abolished when this drug was combined with DHA. These data suggest that the systemic administration of the DHA–indomethacin combination induces a synergistic and gastric safety effect. •Interaction of systemic indomethacin and DHA was evaluated in the formalin test.•Indomethacin – DHA combination resulted in a synergistic antinociceptive effect.•DHA protects against indomethacin-induced gastric injury in the rat.