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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-HT<jats:sub>2<\/jats:sub>receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT<jats:sub>3<\/jats:sub>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.<\/jats:p>","DOI":"10.1155\/2015\/686424","type":"journal-article","created":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T21:06:18Z","timestamp":1433451978000},"page":"1-9","source":"Crossref","is-referenced-by-count":5,"title":["Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms"],"prefix":"10.1155","volume":"2015","author":[{"given":"Norma","family":"Carrillo-Mungu\u00eda","sequence":"first","affiliation":[{"name":"Laboratorio \u201cFarmacolog\u00eda del Dolor\u201d del Centro Universitario de Investigaciones Biom\u00e9dicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma. 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