Malaysian Institute of Pharmaceuticals and Nutraceuticals, Malaysian Ministry of Science, Technology and Innovation, Bukit Gambir, Penang, Malaysia.
PLoS One. 2011;6(12):e28340. doi: 10.1371/journal.pone.0028340. Epub 2011 Dec 21.
A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.
治疗药物成瘾的一个主要障碍是阿片类药物戒断综合征的严重程度,这可能导致不必要的复发。美沙酮是在广泛用于减轻药物戒断痛苦的Mitragyna speciosa 叶片中发现的主要生物碱化合物。进行了一系列实验来研究美沙酮对经历吗啡戒断期的斑马鱼焦虑行为、皮质醇水平和应激途径相关基因表达的影响。成年斑马鱼在 1.5mg/L 的浓度下接受两周的慢性吗啡暴露,然后在测试前进行 24 小时的戒断。通过新的坦克潜水测试,我们首先表明,吗啡戒断的斑马鱼表现出与焦虑相关的游泳行为,例如减少探索行为和增加不稳定运动。吗啡戒断还会升高全身皮质醇水平,这证实了类似应激的表型行为。然而,将吗啡戒断的鱼暴露于美沙酮可减轻大多数与应激相关的游泳行为,并同时降低全身皮质醇水平。通过实时 PCR 基因表达分析,我们还表明,美沙酮在吗啡戒断期间降低了斑马鱼大脑中促肾上腺皮质释放因子受体和前脑啡肽原的 mRNA 表达,这首次揭示了美沙酮在阿片类药物戒断期间减轻焦虑的能力与应激相关的促肾上腺皮质素途径之间可能存在联系。