From the Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Anesthesiology. 2015 Jan;122(1):178-89. doi: 10.1097/ALN.0000000000000434.
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.
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).
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).
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.
曲马多诱发的癫痫可能与血清素综合征在病理上有关。在这里，作者研究了血清素与曲马多致痫潜能之间的关系。
两组大鼠接受预处理以调节大脑中的血清素水平，一组作为假对照（每组 6 只）。血清素调节组接受对氯苯丙氨酸或苯甲酰基色氨酸+5-羟色氨酸治疗。然后通过微透析测量后下丘脑的血清素、多巴胺和组胺水平，同时输注曲马多直至癫痫发作。在另一个实验中，通过向大鼠侧脑室给予 5-羟色胺受体拮抗剂（麦角乙脲）或生理盐水（n = 6），研究曲马多的癫痫发作阈值。
预处理显著影响癫痫发作阈值和血清素波动。在对氯苯丙氨酸组中，阈值降低，在苯甲酰基色氨酸+5-羟色氨酸组中，阈值升高（引起癫痫发作所需的曲马多平均±SEM 量；假对照：43.1±4.2mg/kg，对氯苯丙氨酸：23.2±2.8mg/kg，苯甲酰基色氨酸+5-羟色氨酸：59.4±16.5mg/kg）。在对氯苯丙氨酸组中，基线时的血清素水平及其与曲马多输注的增加较少，而在苯甲酰基色氨酸+5-羟色氨酸组中则较多。此外，癫痫发作阈值与血清素水平呈负相关（相关系数；0.71，P <0.01），而侧脑室麦角乙脲降低了癫痫发作阈值（与生理盐水相比，P <0.05）。
作者确定血清素减少的大鼠易发生曲马多诱导的癫痫发作，并且血清素浓度与癫痫发作阈值呈负相关。此外，5-羟色胺受体拮抗作用引发了癫痫发作的表现，表明曲马多诱导的癫痫发作与血清素综合征不同。
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