Hesperidin produces antinociceptive response and synergistic interaction with ketorolac in an arthritic gout-type pain in rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2011-02, Vol.97 (4), p.683-689
• Main Authors: Martínez, Ana Laura, González-Trujano, Ma. Eva, Chávez, Marco, Pellicer, Francisco, Moreno, Julia, López-Muñoz, Francisco J.
• Format: Article
• Language: English
• Subjects: Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antinociception; Biological and medical sciences; Capsaicin - pharmacology; Chromatography, High Pressure Liquid; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Drug Synergism; Flavonoids; Gout - drug therapy; Hesperidin; Hesperidin - therapeutic use; Inflammatory joint diseases; Ketorolac; Ketorolac - therapeutic use; Lamiaceae; Male; Medical sciences; Metabolic diseases; Miscellaneous; Miscellaneous. Osteoarticular involvement in other diseases; Other metabolic disorders; Pain - chemically induced; Pain - drug therapy; Purines and pyrimidines (gout, hyperuricemia...); Rats; Rosmarinus officinalis; Rosmarinus officinalis L; Rutaceae; Synergism; TRPV1 receptor
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2010.11.010

Hesperidin occurs in greatest concentration in plants from the Rutaceae and Lamiaceae families. In human nutrition it contributes to the integrity of blood vessels and its deficiency in the diet has been linked to abnormal capillary leakiness as well as pain. In this study, the bioflavonoid hesperidin was identified as an active compound in an ethanol extract of the Rosmarinus officinalis aerial parts tested in the pain-induced functional impairment model in the rat (PIFIR) as an assay of inflammatory and chronic nociception similar to that observed in clinical gout. Hesperidin produced a dose-dependent and significant response with an ED 25 = 1666.72 mg/kg in comparison to an ED 25 = 302.90 mg/kg for the extract or an ED 25 = 0.47 mg/kg for the reference drug ketorolac in the PIFIR model. Although the antinociceptive response of R. officinalis was reverted in presence of the opioid antagonist naloxone (10 mg/kg, s.c.) and the 5HT 1A antagonist WAY100635 (0.12 mg/kg, s.c.), the hesperidin response was not modified by naloxone (10 mg/kg), WAY100635 (0.12 mg/kg), bicuculline (1 mg/kg, s.c.), flumazenil (10 mg/kg, i.p.) or caffeine (1 mg/kg, s.c.). Nevertheless, it was reduced in presence of capsazepine (10 or 20 mg/kg, s.c.) suggesting the participation of the TRPV1 receptor, which was reinforced when hesperidin significantly reduced the capsaicin-induced nociceptive response. A synergistic interaction was also observed when antinociceptive doses of hesperidin were combined with those of ketorolac producing 15 combinations mainly in additive and supra-additive responses. These results provide evidence for the antinociceptive activity of hesperidin and demonstrate synergistic response when combined with ketorolac, possibly by involvement of the TRPV1 receptor, suggesting their clinical potential in pain therapy. ► The bioflavonoid hesperidin produces antinociceptive activity in the PIFIR model. ► Hesperidin tested at antinociceptive doses did not cause motor dysfunction in rats. ► TRPV1 receptor is partially involved in the mechanism of action of hesperidin. ► Antinociceptive synergism is obtained when hesperidin is combined with ketorolac.