Dataset Information

Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

ABSTRACT: 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 Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement.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 Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level.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.

SUBMITTER: Khor BS

PROVIDER: S-EPMC3244390 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

Khor Beng-Siang BS Jamil Mohd Fadzly Amar MF Adenan Mohamad Ilham MI Shu-Chien Alexander Chong AC

PloS one 20111221 12

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 p ...[more]

PMID: 22205946

Similar Datasets

Project description:BackgroundMorphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine-induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti-inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress.MethodsTwo animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC-derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini-pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC-derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC-derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation.ResultsIn both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine-induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens.ConclusionData presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.

Project description:Deep brain stimulation (DBS) modulates the neuronal activity in specific brain circuits and has been recently considered as a promising intervention for refractory addiction. The insula cortex is the hub of interoception and is known to be involved in different aspects of substance use disorder. In the present study, we investigate the effects of continuous high frequency DBS in the anterior insula (AI) on drug-seeking behaviors and examined the molecular mechanisms of DBS action in morphine-addicted rats. Sprague-Dawley rats were trained to the morphine-conditioned place preference (CPP, day 1-8) followed by bilaterally implanted with DBS electrodes in the AI (Day 10) and recovery (Day 10-15). Continuous high-frequency (HF) -DBS (130 Hz, 150 ?A, 90 ?s) was applied during withdrawal (Day 16-30) or extinction sessions. CPP tests were conducted on days 16, 30, 40 during withdrawal session and several rats were used for proteomic analysis on day 30. Following the complete extinction, morphine-CPP was reinstated by a priming dose of morphine infusion (2 mg/kg). The open field and novel objective recognition tests were also performed to evaluate the DBS side effect on the locomotion and recognition memory. Continuous HF-DBS in the AI attenuated the expression of morphine-CPP post-withdrawal (Day 30), but morphine addictive behavior relapsed 10 days after the cessation of DBS (Day 40). Continuous HF-DBS reduced the period to full extinction of morphine-CPP and blocked morphine priming-induced recurrence of morphine addiction. HF-DBS in the AI had no obvious effect on the locomotor activity and novel objective recognition and did not cause anxiety-like behavior. In addition, our proteomic analysis identified eight morphine-regulated proteins in the AI and their expression levels were reversely changed by HF-DBS. Continuous HF-DBS in the bilateral anterior insula prevents the relapse of morphine place preference after withdrawal, facilitates its extinction, blocks the reinstatement induced by morphine priming and reverses the expression of morphine-regulated proteins. Our findings suggest that manipulation of insular activity by DBS could be a potential intervention to treat substance use disorder, although future research is warranted.

Dataset Information

Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

Publications

Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets