Hesperidin produces antinociceptive response and synergistic interaction with ketorolac in an arthritic gout-type pain in rats.
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 ED₂₅=1666.72 mg/kg in comparison to an ED₂₅=302.90 mg/kg for the extract or an ED₂₅=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.
Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Av. Mexico-Xochimilco No. 101, Col. San Lorenzo Huipulco 14370, México, D.F., México.
Ana Laura
AL
Martínez
Ma Eva
ME
González-Trujano
Marco
M
Chávez
Francisco
F
Pellicer
Julia
J
Moreno
Francisco J
FJ
López-Muñoz
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002211:Capsaicin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006073:Gout / Q000188:drug therapy*; D006569:Hesperidin / Q000627:therapeutic use*; D020910:Ketorolac / Q000627:therapeutic use*; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006569:Hesperidin; D002211:Capsaicin; D020910:Ketorolac