alireza parvizpur

As a major concern for the clinicians, better treatment of the patients hospitalized to quit opioid abuse has always been a target for the researchers working in this field. On the other hand, therapeutic potentials of medicinal plants are greatly becoming of interest to both researchers and consumers in recent years. Among the plants, we can mention those belonging to the genus Marrubium, which has been reported to exert many therapeutic outcomes. The aim of this research was to investigate the effect of Marrubium parviflorum on morphine withdrawal syndrome and the possible relationship with malondialdehyde (MDA), the indicator for lipid peroxidation which is elevated during the syndrome. To perform this study, 48 rats were divided into 6 groups as follows: 1) Saline-Saline 2) Saline-Morphine; 3, 4, 5) Different doses of the extract-Morphine (10, 20 and 40 mg.kg-1); 6) The most effective dose of the extract-Saline. In order to evaluate withdrawal syndrome, the increasing doses of morphine were injected subcutaneously for 9 days followed by a single dose of naloxone (4 mg.kg-1, i.p.). Then the withdrawal symptoms was evaluated and total withdrawal score (TWS) was calculated. On the other hand, in order to confirm the effectiveness biochemically and to investigate the possible relationship between the observed effects and lipid peroxidation, blood samples were collected for malondialdehyde (MDA) measurement. According to the data, administration of the extract (in two higher doses) alleviated the syndrome-related behavioral signs as well as MDA levels significantly. Altogether, based on the results, aerial parts of Marrubium parviflorum seem to be beneficial for coping better with morphine withdrawal syndrome through complex pathways such as suppressing lipid peroxidation, further preclinical and clinical studies are required in this regard though.

Antioxidant drugs may be useful in preventing morphine-induced dependency bysuppressing oxidative stress. Vitamin E which has many essential roles in the body is a powerfulantioxidant. On the other hand, selenium is an essential trace element that plays a strong rolein various biochemical pathways. The aim of this study was to investigate the effects of sodiumselenite and vitamin E on morphine-induced dependency in mice.

Ninety male mice, weighing 20 to 30 g, were randomly divided into 10 groups and weretreated as follows: a) saline and b) morphine groups were pretreated (for 2 days) with normalsaline (10 ml.kg-1.day-1, ip) then daily doses of normal saline (10 ml.kg-1.day-1, ip) and morphine(50 mg.kg-1.day-1) were added to the injections for the following 4 days, respectively. c, d, e)sodium selenite, f, g, h) vitamin E, i) vitamin E solvent (almond oil) and j) co-administrationgroups were pretreated (for 2 days) with sodium selenite (0.25, 0.5, 1 mg.kg-1.day-1, ip), vitaminE (20, 40, 60 IU.kg-1.day-1, ip), vitamin E solvent (10 ml.kg-1.day-1, ip) and combination of thedrugs respectively, then morphine doses (50 mg.kg-1.day-1, ip) were added to the injections forthe following 4 days. Withdrawal symptoms were evaluated after injecting naloxone (4 mg/kg/day). Biochemical evaluations were also performed.

The results showed that co-administration of sodium selenite and vitamin E (at lowdoses) significantly reduced morphine dependency (p < 0.05).

The synergistic effect of sodium selenite and vitamin E can be a suitable andefficient approach to reduce dependency.

Among various neurological systems involved in the development of morphine tolerance, serotonergic and adrenergic systems are very significant. In this study, we used duloxetine to further investigate the association between serotonergic and noradrenergic systems and the occurrence of opioid tolerance.

Six groups of male Wistar rats were studied including saline, morphine, morphine + duloxetine (15, 30, and 60mg.kg–1.day–1), and duloxetine-treated groups. Base latency time (BL) was determined using hot plate test (50 ± 0.5ºC). The latency times were reported as MPE% (maximum possible effect) and AUC (area under the curve) was calculated for each MPE%-Time curve (to evaluate global analgesic effect).

Morphine-treated group showed tolerance on the 9th day. As the same way, the groups treated with morphine and duloxetine (15, 30, 60mg/kg) showed tolerance on the 13th, 17th, and 23rd days, respectively. Duloxetine-treated group was tolerated on the 11th day. There was a significant difference between the mean AUC in morphine + duloxetine (60mg/kg-1/day–1) and morphine-treated groups.

Previous studies revealed that chronic administration of morphine would reduce serotonin release in the central nervous system (CNS). This study showed the effective role of duloxetine and the serotonergic system in postponing the tolerance to analgesic effects of morphine.

Long-term exposure to opioids may lead to physical dependence and tolerance. The purpose of this study was to investigate the effects of Citrus aurantium essential oil (CEO) on the morphine-induced tolerance and dependence. To evaluate morphine tolerance, the experiments were carried out in 6 rat groups (n=8) in the weight range of 225-275 g. The control group received morphine (10 mg/kg/day) and the test groups received morphine with the different doses of essential oil (CEO 20, 40 and 80 mg/kg/day) or 4 mL/kg of essential oil vehicle (KolliphorÒ HS15 30% in normal saline that adjusted in pH=7.4 with phosphate buffer) intraperitoneally. The hot-plate test was carried out every other day, 90 minutes after the injections. To examine morphine withdrawal, male Wistar rats were divided into seven groups (n=8) randomly, including: morphine sulphate, CEO (20, 40 and 80 mg/kg) + morphine, vehicle of CEO + morphine. The rats were rendered morphine-dependent by injection of additive doses of morphine subcutaneously for 9 days. The procedure of the morphine administration was as following protocol: day1: 5 mg/kg/12h, day 2 and 3: 10 mg/kg/12h, day 4 and 5: 15 mg/kg/12h, day 6 and 7: 20 mg/kg/12h and day 8 and 9: 25 mg/kg/12h. In the 9th day, 2 hours after the last dose of morphine, naloxone (4 mg/kg) was injected intraperitoneally. Some withdrawal behaviors were counted for 60 minutes. Morphine tolerance was completed after 5 days in the control group. The vehicle group showed tolerance on the 9th day (p-value=0.991), 20mg group in the 13th day (p-value to control=0.010, to vehicle=0.049), 40 mg group on the 15th day (p-value to control and vehicle<0.001) and 80 mg group on the 13th day (p-value to control= 0.001, to vehicle= 0.007). The results showed that CEO could reduce the morphine withdrawal syndrome and total withdrawal score (TWS). Intraperitoneally injection of CEO in two doses (40 mg/kg with p<0.001 and 80 mg/kg with p<0.01) significantly reduced the TWS in comparison to the morphine+vehicle treated group. The results indicated that chronic administration of C. aurantium essential oil extracted had beneficial effects in reducing morphine withdrawal syndrome and could significantly delay tolerance to morphine.

Thioridazine (TZ) is used mainly in the treatment of schizophrenia. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. In this context, we examined the cytotoxic mechanisms of TZ on freshly isolated rat hepatocytes to better understanding of the pathogenesis of TZ-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. The level of parameters such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosomal membrane integrity and cellular glutathione (GSH) content in TZ-treated and non-treated hepatocytes were determined and the mentioned markers were assessed in the presence of Coenzyme Q10 and/or melatonin.
Results showed that TZ caused an increase in ROS formation as well as induction of LPO and GSH depletion. Moreover, mitochondria and lysosomes seem to be targets of TZ-induced toxicity. The administration of Coenzyme Q10 and/or melatonin efficiently decreased the rate of ROS formation, LPO and improved cell viability, MMP, GSH level and lysosome membrane integrity. This study proposes the possible protective role of Coenzyme Q10 and/or melatonin against TZ-induced cellular injury probably through their radical scavenging properties and their effects on mitochondria and lysosomes.

Clinical use of Morphine in pain management is a controversial issue and long-term exposure to opiates induces physical dependency and tolerance. The aim of this study was to evaluate the attenuation effects of Magnesium sulfate and Amitriptyline on the development of Morphine-induced dependency and tolerance. In this study different groups of mice were received saline (10 mL/kg,ip), Morphine (50 mg/kg,ip), Magnesium sulfate (20, 40 and 60 mg/kg,ip), Amitriptyline (5, 10 and 15 or 20 mg/kg,ip), or combination of Magnesium sulfate (20 mg/kg,ip) and Amitriptyline (5 mg/kg,ip) once a day for 4 and 10 continues days, respectively for investigation of the effects of Magnesium sulfate and Amitriptyline on the prevention of dependency and tolerance. Tolerance was assessed by administration of Morphine (9 mg/kg,ip) and using hot plate test on eleventh day. Withdrawal symptoms were assessed in fifth day by administration of naloxone (4 mg/kg,ip), 2 hrs after last dose of Morphine during 30 minutes for each animal. It was found that pretreatment with Magnesium sulfate or Amitriptyline decreased the development of tolerance to the antinociceptive action of Morphine and also reduced naloxone-precipitated withdrawal jumps and standing on feet. Additionally, pretreatment by co-administration of Magnesium sulfate and Amitriptyline, before morphine administration, decreased the dependency and tolerance more significantly. From these results it could be concluded that pretreatment of Magnesium sulfate via blocking the N-methyl-D-Aspartate receptor-operated calcium channel and Amitriptyline by Glutamate transporter activation property alone or in combination could prevent the development of Morphine-induced dependency and tolerance.

Opioidal analgesics are one of the most important drugs that have been widely used in attenuating moderate to severe pain. Unfortunately, the problems of opioids long term usage are tolerance, dependence, and ultimately addiction to mentioned drugs. Glial cells (microglia and astrocyte) and pro-inflammatory cytokines are important factors in morphine tolerance and withdrawal symptoms. It has been demonstrated that Artemisia austriaca extract has got antinociceptive and anti inflammatory properties. In this study the effect of total methanolic extract of aerial parts of Artemisia austrica on withdrawal syndrome of morphine in male rats has been evaluated. Adult male Wistar rats were rendered morphine-dependent by injection of additive doses of morphine subcutaneously twice daily for 9 days. To determine the effect of Artemisia austriaca extract on morphine withdrawal syndrome, 1 hours after last morphine injection, different doses of the methanolic extract of Artemisia austriaca (100, 200, 400 mg/kg, i.p.) dissolved in its vehicle (%25 DMSO in saline), was injected and after 30 minutes, naloxone (4 mg/kg, i.p.) was injected and withdrawal signs were recorded for 45 minutes. The results showed that methanolic extract of Artemisia austriaca could reduce the morphine withdrawal symptoms in a dose-dependent manner. Conclution: The results of the present study indicate that Artemisia austriaca has beneficial effects in reducing withdrawal syndrome of morphine. The underlying mechanisms of this effect may consist of reduction of inflammatory response and attenuating of pro-inflammatory cytokines activation by its alkaloids content.