Effects of Thymbra spicata extract and Thymol on morphine withdrawal syndrome in mice (insights to the liver function, antioxidant, and behavioral responses).

Safe chemicals for drug withdrawal can be extracted from natural sources. This study investigates the effects of clonidine and Thymbra spicata extract (TSE) on mice suffering from morphine withdrawal syndrome. Thymol, which is the active constituent in TSE, was also tested. A total of 90 mice were divided into nine groups. Group 1 was the control group, while Group 2 was given only morphine, and Group 3 received morphine and 0.2 mg/kg of clonidine. Groups 4-6 were given morphine along with 100, 200, and 300 mg/kg of TSE, respectively. Groups 7-9 received morphine plus 30, 60, and 90 mg/kg of Thymol, respectively, for 7 days. An oral naloxone challenge of 3 mg/kg was used to induce withdrawal syndrome in all groups. Improvement of liver enzyme levels (aspartate aminotransferase, alkaline phosphatase, and alanine transaminase) (p < .01) and behavioral responses (frequencies of jumping, frequencies of two-legged standing, Straub tail reaction) (p < .01) were significantly observed in the groups receiving TSE and Thymol (Groups 4-9) compared to Group 2. Additionally, antioxidant activity in these groups was improved compared to Group 2. Nitric oxide significantly decreased in Groups 4 and 6 compared to Groups 2 and 3 (p < .01). Superoxide dismutase increased dramatically in Groups 5, 8, and 9 compared to Groups 2 and 3 (p < .01). Groups 5-9 were significantly different from Group 2 in terms of malondialdehyde levels (p < .01). Certain doses of TSE and Thymol were found to alleviate the narcotics withdrawal symptoms. This similar effect to clonidine can pave the way for their administration in humans.

Transgenerational consequences of prepregnancy chronic morphine use on spatial learning and hippocampal Mecp2 and Hdac2 expression.

There has recently been increasing interest in the transgenerational effects of opioids. Herein, transgenerational consequences of maternal chronic morphine consumption before gestation were investigated at the behavioral and molecular levels of next two generations. Twelve female Wistar rats were randomly divided into two groups: pregestation morphine-consuming and control mothers. Morphine-consuming mothers had access to morphine solution ad libitum for 2 months, whereas the control mothers received only tap water. One month after stopping morphine consumption, rats were mated. After parturition, male and female offspring and later grandoffspring of morphine-consuming and control mothers were divided and used as the study groups. Behavioral testing comprised spatial memory assessment using Morris water maze. Hippocampal expressions of Mecp2 and Hdac2 were investigated through real-time PCR. Spatial memory was significantly diminished in male but not female offspring and grandoffspring of morphine-consuming mothers versus control (P<0.01). Hippocampal Mecp2 and Hdac2 were significantly upregulated in male but not in female offspring and grandoffspring of morphine-consuming mothers compared with control (P<0.05). Consequences of prepregnancy morphine consumption have sex differences and are detectable at the behavioral and molecular level over at least the next two generations.

Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence.

BACKGROUND: TNF-α and S100B are important signaling factors that are involved in many aberrant conditions of the brain. Chronic morphine exposure causes aberrant modifications in the brain. OBJECTIVES: We examined the consequences of chronic morphine consumption by parents before mating on hippocampus TNF-α and S100B levels in the parents and their offspring. METHODS: A total of 12 adult female and 12 adult male Wistar rats were used as parents. Each gender was divided randomly into two groups: control and morphine consumer. Morphine consumer groups received morphine sulfate dissolved in drinking water (0.4 mg/ml) for 60 days. Control groups received water. Thirty days before mating, morphine was replaced with water. All offspring also received water. The hippocampus of both parental and offspring groups was extracted to measure TNF-α and S100B levels using an ELISA. RESULTS: Hippocampus TNF-α levels were significantly increased due to chronic morphine use in both male and female parents compared to those of control parents (P < 0.01). Moreover, both male and female offspring of morphine-exposed parents showed a significant increase in hippocampus TNF-α levels compared to those of control offspring (P < 0.01). Hippocampus levels of S100B were significantly decreased in male (P < 0.05) but not female morphine consumer parents relative to control parents. Both male and female offspring of morphine-exposed parents showed significant decreases in hippocampus S100B levels (P < 0.05) compared to those of control offspring. CONCLUSIONS: The consequences of chronic morphine use by parents, even when it is stopped long before mating and pregnancy, could induce modifications in the hippocampus of the next generation.