title: Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.
abstract: BACKGROUND
  Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol.
  
  
  METHODS
  Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6).
  
  
  RESULTS
  Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P < 0.01), while intracerebroventricular methysergide lowered the seizure threshold (P < 0.05 vs. saline).
  
  
  CONCLUSIONS
  The authors determined that serotonin-reduced rats were predisposed to tramadol-induced seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.
authors.affiliation: From the Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Funao
authors.forename: Koichi
authors.initials: K
authors.lastname: Suehiro
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Kiyonobu
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D020230:Serotonin Syndrome / Q000378:metabolism*; D014147:Tramadol
chemical_list: D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D014147:Tramadol; D006632:Histamine