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Planta Med 2014; 80(02/03): 139-145
DOI: 10.1055/s-0033-1360220
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Isobolographic Analysis of the Antinociceptive Interaction between Ursolic Acid and Diclofenac or Tramadol in Mice

Myrna Déciga-Campos
1   Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México D. F., México
,
Alejandra Cortés
1   Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México D. F., México
2   Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz”, México D. F., México
,
Francisco Pellicer
2   Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz”, México D. F., México
,
Irene Díaz-Reval
3   Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
,
María Eva González-Trujano
2   Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz”, México D. F., México
› Author Affiliations
Further Information

Publication History

received 26 March 2013
revised 22 November 2013

accepted 02 December 2013

Publication Date:
15 January 2014 (online)

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Abstract

It is considered that natural products used in folk medicine can potentiate the effect of drugs. The aim of this study was to evaluate the pharmacological interaction between ursolic acid, a triterpene isolated from herbal medicines to treat pain, and the analgesics diclofenac or tramadol. Individual dose-response curves of the antinociceptive effect of these compounds were built to calculate the ED50, as well as the pharmacological interaction, by using isobolographic analysis. All treatments decreased significantly and in a dose-dependent manner the writhing behavior with ED50 values of 103.50 ± 19.66, 20.54 ± 6.05, and 9.60 ± 1.69 mg/kg, for ursolic acid, diclofenac, and tramadol, respectively. An isobolographic analysis allowed the characterization of the pharmacological interaction produced by a fixed ratio combination of 1 : 1 and 1 : 3 of equi-effective doses of these compounds. Theoretical antinociceptive ED50 values of ursolic acid–diclofenac were 62.12 ± 10.28 and 41.43 ± 6.69 mg/kg, respectively, not statistically different from those obtained experimentally (44.52 ± 5.25 and 44.89 ± 49.05 mg/kg, respectively), reporting an additive interaction. Theoretical antinociceptive ED50 values of ursolic acid–tramadol (56.56 ± 9.87 and 33.08 ± 5.07 mg/kg, respectively) were significantly lower than those observed experimentally (138.36 ± 49.05 and 67.34 ± 18.98 mg/kg, respectively) reporting antagonism in this interaction. Antinociceptive response obtained from isobolograms in the writhing test was corroborated by using formalin test in mice. Adverse effects such as gastric damage in the ursolic acid–diclofenac combination did not increase in an additive form similarly as with antinociception. Conversely, sedative response was significantly increased in the ursolic acid–tramadol combination. As observed in the formalin test, the antagonism on the antinociceptive response between ursolic acid and tramadol (1 : 1) was not reverted in the presence of the opioid antagonist naltrexone (1 mg/kg, i. p.). These results provide evidence for a differential pharmacological interaction, in which ursolic acid does not interfere with the antinociceptive effect of diclofenac but antagonizes that obtained with tramadol in an independent opioid mechanism. Therefore, medicinal plants containing abundant presence of ursolic acid may also modify efficacy in the alternative combinations for the pain therapy.

Key words

antinociception - diclofenac - isobologram - synergism - tramadol - ursolic acid
 

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