title: Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms.
abstract: 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.
authors.affiliation: Laboratorio "Farmacología del Dolor" del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico.
authors.forename: Norma
authors.initials: N
authors.lastname: Carrillo-Munguía
authors.affiliation: Laboratorio 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.
authors.forename: Ma Eva
authors.initials: ME
authors.lastname: González-Trujano
authors.affiliation: Unidad de Investigación Dr. Enrico Stefani del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Huerta
authors.affiliation: Unidad de Investigación Dr. Enrico Stefani del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico.
authors.forename: Xochitl
authors.initials: X
authors.lastname: Trujillo
authors.affiliation: Laboratorio "Farmacología del Dolor" del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Avenida 25 de Julio 965, 28045 Colima, COL, Mexico.
authors.forename: M Irene
authors.initials: MI
authors.lastname: Díaz-Reval
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007650:Ketanserin / Q000008:administration & dosage; D009270:Naloxone / Q000008:administration & dosage; D017294:Ondansetron / Q000008:administration & dosage; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D014147:Tramadol / Q000008:administration & dosage*
chemical_list: D000701:Analgesics, Opioid; D009270:Naloxone; D014147:Tramadol; D002110:Caffeine; D017294:Ondansetron; D007650:Ketanserin