Preventive Effect of Maternal Forced Exercise on Offspring Pain Perception and Intensity: The Role of 5-HT2 and D2 Receptors.

BACKGROUND: Many previous studies showed that maternal forced exercise can reduce some central disorders in offsprings, but its clear mechanism remains unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise in offspring neurodevelopment and effect on some behaviors were evaluated. MATERIALS AND METHODS: Forty-eight pregnant rats were trained by forced exercise, and some behavioral assays in their offspring were performed in the presence and absence of 5-HT2 and D2 receptor antagonists in various experimental groups. RESULTS: Our data showed that maternal forced exercise caused increase in latency of pain perception in offsprings in hot plate test, writhing test (WT), and tail flick test. Furthermore, a decrease in intensity was shown by WT. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists could inhibit these effects of forced exercise and cause disturbances in pain perception and intensity. CONCLUSION: Our data suggested that maternal forced exercise causes protective effects on offspring pain perception and intensity, and in this effect, 5-HT2 and D2 receptors are probably involved.

The effect of maternal forced exercise on offspring pain perception, motor activity and anxiety disorder: the role of 5-HT2 and D2 receptors and CREB gene expression.

The effect of maternal forced exercise on central disorders in offsprings has been shown but the mechanism is still unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise on offspring neurodevelopment and neurobehavioral symptoms is evaluated. Sixty pregnant rats were trained by forced exercise and some behavioral and molecular aspects in their offspring were evaluated in presence of 5-HT2 and D2 receptors agonists and antagonists. The results showed that maternal forced exercise causes increase of pain tolerability and increase latency of pain perception in offspring in hot plate test, writhing test and tail flick test. Also maternal forced exercise causes decrease of depression and anxiety like behavior in offsprings. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists inhibited the protective effects of forced exercise and cause disturbance in pain perception and tolerability and increase depression and anxiety in offsprings. Also expression of cyclic AMP response element binding protein (CREB) was changed in all experimental groups. In conclusion, our data suggested that maternal forced exercise causes neurobehavioral protective effect on offsprings and this effect might probably be mediated by 5-HT2 and D2 receptors and activation of CREB gene expression.

Attenuation of morphine physical dependence and blood levels of cortisol by central and systemic administration of ramelteon in rat.

BACKGROUND: Chronic administration of morphine cause physical dependence but the exact mechanism of this phenomenon remains unclear. The aim of this study is the assessment of systemic and intracerebroventricular (icv) administration of ramelteon (a melatonin receptor agonist) on morphine physical dependence. METHODS: 88 adult male rats were divided into 2 major groups, namely "systematic" and "central" administration of ramelteon. In the first category, systemic administration of ramelteon at various dosages (10, 20, and 40 mg/kg) was assessed on dependent animals and withdrawal signs were compared with positive (received morphine and saline as systemic administration), negative control (saline) and group under treatment by ramelteon (40 mg/kg) groups. In the second category, central administration of ramelteon at various dosages (25, 50, or 100 µg,) was assessed on dependent animals and withdrawal signs were compared with the positive control (received morphine and saline as icv) and negative control (saline) groups, and the group under treatment by ramelteon (50 µg/5 µl/rat). On the test day, all animals received naloxone (3 mg/kg) and were observed for withdrawal signs. Total withdrawal score (TWS) was also determined. Finally, to evaluate the stress level of dependent rats, blood cortisols were measured. RESULTS: Central administration of ramelteon in all doses and systemic administration in high doses attenuate withdrawal syndrome in comparison with the dependent positive control group (P<0.05). Both central and systemic administrations of ramelteon can attenuate the blood cortisol level in comparison with the dependent positive control group (P<0.05). CONCLUSION: In conclusion, we found that central administration of ramelteon attenuated morphine withdrawal symptoms and cortisol level as a stress marker.

Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam.

Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 groups, from which 4 groups became dependent to alcohol (2 g/kg/day) for 15 days. From day 16, treatment groups were treated by diazepam (0.5mg/kg), forced exercise, and diazepam (0.5 mg/kg) concurrent with forced exercise for two weeks; And the positive control group received same dose of alcohol (2 g/kg/day) for two weeks. The negative control group received normal saline for four weeks. Finally, on day 31, all animals were observed for withdrawal signs, and Alcohol Total Withdrawal Score (ATWS) was determined. Blood cortisol levels were measured in non-fasting situations as well. Present findings showed that ATWS significantly decrease in all treatment groups in comparison with positive control group (P<0.05 for groups received diazepam and treated by forced exercise and P<0.001 for group under treatment diazepam + forced exercise). Moreover, blood cortisol level significantly decreased in all treatment groups (P<0.001). This study suggested that forced exercise and physical activity can be useful as adjunct therapy in alcoholism and can ameliorate side effects and stress situation of withdrawal syndrome periods.

The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.

Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1ß and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration.

Attenuation of morphine withdrawal syndrome by various dosages of curcumin in comparison with clonidine in mouse: possible mechanism.

BACKGROUND: Herbal medical compounds and their major constituent have been used in the management and treatment of opioid withdrawal syndrome and pain. This study was carried out to clarify the effect of curcumin, the major compound of turmeric, on morphine withdrawal syndrome in mouse model and its possible mechanisms of pain relieving activity by assessing in writhing test as a model of visceral pain. METHODS: Due to two separate protocols (withdrawal syndrome and pain), 144 male albino mice were divided in two major groups. In withdrawal syndrome group, test effect of various dosages of curcumin (10, 20, and 40 mg/kg) was assessed on withdrawal signs and compared with positive and negative control and standard treatment (clonidine 0.4 mg/kg) groups. In pain groups, to determine the mechanism of pain relieving activity of curcumin, various dosages of curcumin (10, 20, and 40 mg/kg) in three separated groups, were used against acetic acid induced writhing (which is a constriction) test. The most effective dose (40 mg/kg) was used in writhing test and compared with groups pretreated with antagonist of major neurotransmitters involved in pain; and compared with group pretreated with vehicle (DMSO, 0.05%) as control. RESULTS: Curcumin attenuates withdrawal syndrome in a dose dependent manner in comparison with the dependent positive control group (P<0.05). It also indicated that pretreatment with naloxone and cyproheptadine significantly attenuate antinociception effect of curcumin (P<0.05). CONCLUSION: This study advocate that antinociception of curcumin was mediated by opioidergic and adrenergic system.

Protective effects of various dosage of Curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus.

BACKGROUND: During recent years, the defensive role of Curcumin against oxidative stress and apoptosis has been experimentally documented. Long term consumption of morphine induces apoptosis and oxidative stress which may cause serious damage to brain cells. To investigate whether Curcumin could protect rat's hippocampus against morphine induced destruction, we assessed isolated hippocampus cells for oxidative stress, anti oxidant factor and apoptotic factor activities. METHODS: For this, 40 adult male rats were taken and randomly allocated to one of the five groups. Groups 1 and 2 received morphine (45 mg/kg) and normal saline (0.2 ml/rat) respectively for four weeks. Groups 3, 4 and 5 concurrently were treated with morphine (45 mg/kg, sc) and Curcumin (10, 20 and 40 mg/kg) for four weeks. RESULTS: The results showed that morphine significantly increased lipid peroxidation, mitochondrial GSH level, concentration of Bax; caspase-3 and caspase-9 activities while decreasing Bcl-2 concentration. Further, a significant decrease in superoxide dismutase and glutathione peroxidase activity was also observed. Various dosage of Curcumin attenuated these effects by significantly lowering lipid peroxidation, GSSG level, Bax concentration, caspase-3 and caspase-9 activities, while increasing superoxide dismutase and glutathione peroxidase activity, GSH level and Bcl-2 concentration. CONCLUSIONS: These findings have demonstrated that Curcumin can act as an antioxidant and antiapoptotic agent against damage induced by morphine dependence.

Preventive Effects of Forced Exercise against Alcohol-induced Physical Dependency and Reduction of Pain Perception Threshold.

BACKGROUND: Treatment of postabstinence syndrome of alcohol is one of the major strategies of alcoholism treatment. Exercise can be modulated major brain pathways such as a reward system and pain perception centers. The aim of this study was to evaluation the effects of forced exercise in the management of alcohol dependence and pain perception alteration which induced by alcoholism. METHODS: 72 adult male rats were divided into 2 major groups: (1) 40 of them was divided into groups of positive control (alcohol dependent) negative control and alcohol dependent groups under treatment by forced exercise, diazepam (0.4 mg/kg) and forced exercise in combination with diazepam and alcohol withdrawal signs, and blood cortisols, were measured in this groups. (2) 32 rats were divided into control, alcohol dependent (without treatment), and alcohol-dependent groups under treatment by forced exercise or indometacin (5 mg/kg) and then pain perception was assessed by using writhing test, tail-flick and hot plate test. RESULTS: Forced exercise, diazepam, and their combinations significantly attenuates withdrawal syndrome to 20 ± 2, 22 ± 1.3 and 16 ± 2 and blood cortisol level to 6.8 ± 1.3,7.9 ± 1.2 and 5.8 ± 1.1, respectively, in comparison with the positive control group (P < 0.05 and P < 0.001). In alcohol dependent animal under treatment by forced exercise, pain response significantly inhibited with 37%, 57% and 38% decreases in writhing test, hot plate, and tail-flick test, respectively, in comparison with alcohol dependent (without treatment) group (P < 0.05). CONCLUSIONS: This study suggested that forced exercise can be useful as adjunct therapy in alcoholism patient and also can be effective in modulation of pain threshold reduction that was induced by alcohol dependency.

Attenuation of morphine withdrawal signs, blood cortisol and glucose level with forced exercise in comparison with clonidine.

BACKGROUND: Morphine withdrawal usually results in undesired outcomes, despite partial benefits of alternative medication such as methadone, because of the lack of mental sedation during the withdrawal period, may not lead to the desired result. In this study, forced exercise by treadmill is used to manage morphine dependence in animal model. MATERIALS AND METHODS: Forty adult male mice were divided into 5 groups, from which 4 groups became dependent by increasing daily doses of morphine for 6 days (20-45 mg/kg, SC). Afterwards, the animals were treated for 21 days by either of the following protocol: Positive control (dependent) received once daily 45 mg/kg of morphine sulfate (SC) for 21 day, group under treatment by clonidine (0.4 mg/kg, SC) for 21 day group under treatment by forced exercise by treadmill for 21 day, group under treatment by combination of clonidine (0.4 mg/kg, SC) and forced exercise by treadmill for 21day and the negative control group(independent) received saline injection like other groups. Each of this administration was injected at 8 AM. Finally, in the test day (day 28), all animals received a single dose of naloxone (3 mg/kg, SC) at 8 AM and then were observed for withdrawal signs, and Total Withdrawal Score (TWS) was determined as described previously. After withdrawal sign evaluation for evaluation of stress level of dependent mice, blood cortisol and glucose level were measured in non-fasting situations well. RESULTS: This study showed that TWS significantly decreased in all treatment groups in comparison with positive control group (P < 0.001). Moreover, blood cortisol and glucose level significantly decreased in group under treatment by clonidine (0.4 mg/kg) and group under treatment by combination of clonidine (0.4 mg/kg) and forced exercise by treadmill groups in comparison with control positive (dependent) (P < 0.05). CONCLUSION: This study suggested that forced exercise can be useful as adjunct therapy in dependent people and can ameliorate side effects and stress situation of withdrawal syndrome periods.