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BioMed Research International
Volume 2015 (2015), Article ID 686424, 9 pages
Research Article

Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms

1Laboratorio “Farmacología del Dolor” del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico
2Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, 14370 México City, DF, Mexico
3Unidad de Investigación Dr. Enrico Stefani del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico

Received 26 January 2015; Revised 15 May 2015; Accepted 17 May 2015

Academic Editor: Kouichiro Minami

Copyright © 2015 Norma Carrillo-Munguía et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception.