Introduction: Antidepressants can modulate brain monoamines by acting on pre-synaptic and postsynaptic receptors. Autoreceptors can reduce the monoamines effect on the somatodendritic or pre-synaptic regions despite its postsynaptic counter effects. The direct effect of some antidepressants is related to its temporal and spatial bioavailability in the vicinity of these receptors (still a matter of controversies). This research evaluated the direct effect of acute bupropion on the Ventral Tegmental Area (VTA) dopaminergic neuronal firing rate.
Methods: Male Wistar rats were divided into intracerebroventricular and microiontophoretic groups with 14 subgroups (n=5 in each subgroup). Amounts of 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 mol of bupropion (5 μL/3 min) were microinfused to the first group and then the ejected amounts of bupropion at -500, -300, -150, -50 nA of electrical currents (1 mol, pH=4.5, 5 min) were applied to the second group. The control and sham subgroups were studied in each group, too. The units with stable firing rates were extracted, and the effect of bupropion was evaluated statistically with a P value less than 0.05 as the level of significance.
Results: The highest amount of bupropion in the intracerebroventricular application could excite 42% of the neurons and inhibit 56% of them, but the highest amount of microiontophoretic application of bupropion could inhibit 97.5% of the neurons. The neuronal response to bupropion was dose-dependent in all treated groups.
Conclusion: The dual effects of intracerebroventricular bupropion on the VTA dopaminergic neurons but solo inhibitory effect of its microiontophoretic application reflect the intra-VTA and extra-VTA heterogenic cellular and molecular control over the dopaminergic outflow that can be mediated by different receptors. The dopamine autoreceptors on the VTA dopaminergic neurons have complex modulatory effects on the dopaminergic response.
Introduction: Some evidence demonstrates endogenous inhibitory pathways of pain involved in the interphase (phase between early and later phase) of the formalin test. We previously showed that swimming stress modulates the pain-related behaviors during the interphase of the formalin test. In this study, we evaluated the role of the endogenous opioid system in modulating nociceptive responses of the formalin test.
Methods: Swim stress was performed in different heights of water (5, 25, 50 cm) in a swimming tank. The mean nociceptive scores were measured during phase 1 (1-7 min), interphase (8-14 min), and phase 2 (15-90 min) of the formalin test. Opioid receptor antagonist, naloxone (3 mg/kg; IP) was injected immediately before swim stress.
Results: Swim stress attenuated nociceptive behaviors in the first phase and increased the duration of interphase in the formalin test in a water-height-dependent manner, compared to the control group. Naloxone significantly increased nociceptive behaviors in the first phase, interphase, and the second phase of the formalin test, compared to the control group.
Conclusion: Stress could affect the nociceptive response. Swim stress in different heights of water could have different effects on the nociception in different phases of the formalin test. In addition, the involvement of the endogenous opioid system is further demonstrated in the swim stress-induced modulation of pain behaviors in phase 1, phase 2, as well as interphase of formalin test in rats.
Introduction: Methamphetamine (Meth) and Buprenorphine (BUP) modulate pain perception. However, the antinociceptive effects of their interactions, which affect through different systems, are unclear in rats. This study aimed to compare the analgesic effects of Meth, BUP, and their coadministration, as well as the effect of withdrawal from these substances on nociception in male rats.
Methods: In this experiment, 40 male Wistar rats (weight: 250-300 g) were categorized into four groups: control, Meth, BUP, or BUP+Meth. After seven days of treatments, the antinociceptive effects were assessed using the hot plate and the tail flick tests. The differences among the groups were analyzed with ANOVA and Tukey’s post hoc tests. P values less than 0.05 were considered significant.
Results: Meth and BUP increased the reaction times during the hot plate and tail flick tests. The combination of Meth and BUP increased reaction time more than Meth or BUP alone.
Conclusion: The significantly high reaction times in rats treated with Meth and BUP indicate that these substances have antinociceptive effects. In addition, Meth enhanced the antinociceptive effects of BUP. These synergistic effects might occur through the dopaminergic, serotonergic, and or adrenergic systems.
Introduction: Opioid addiction is an important concern in the World. Reports demonstrate that substance use disorder could influence genetic and environmental factors, and children of addicts have a higher rate of psychopathology. In this study, we investigated depression-like behavior among offspring of morphine-exposed rat parents.
Methods: Adult male and female Wistar rats received morphine for 21 consecutive days and then let them were free of drugs for ten days. Offspring of these rats were divided into three distinct groups: maternal morphine-exposed, paternal morphine-exposed, and both maternal and paternal morphine-exposed. We used sucrose preference and Forced Swim Test (FST) to measure depression-like behavior. Also, we induced chronic mild stress using repeated corticosterone injection and evaluated depression-like behavior in offspring of morphine-exposed parents compared with offspring of healthy ones.
Results: Results indicated that depression-like behaviors in the offspring of morphine-exposed rats were higher than those in the offspring of the control group in confronting with chronic mild stress. Additionally, mild chronic stress can produce an exaggerated effect on depression-like behavior in offspring of the morphine-exposed parent(s) compared with those of the control group.
Conclusion: Our data support the previous hypothesis that the depression rate is higher in the children of addicts. We verified that even when mother or father was clean of opioid in the time of gestation, their children would be susceptible to depression. Dysregulation of hypothalamic-pituitary-adrenal axis and changing in neuronal features in the hippocampus increased depression-like behavior in the offspring of morphine-exposure parents.
Introduction: Peripheral nerve injury is one of the most common damages that lead to physical disability. Considering the similarity between the coatings of skeletal muscles and nerve fibers, we conducted this research to determine the effect of muscle graft with Nerve Growth Factor (NGF) and Laminin (L) on nerve repair.
Methods: We cut a 10-mm length of the sciatic nerve from 42 female Wistar rats (Weight: 200±250 g) and equally divided the rats into three groups. In the muscle graft+NGF+laminin group, the degenerated skeletal muscle was sutured with proximal and distal ends of the transected sciatic nerve. Then, NGF (100 ng) and laminin (1.28 mg/mL) were injected into the muscle graft. In the muscle graft group, normal saline was injected into the muscle graft. In the control group, 10 mm of the sciatic nerve was removed without any treatment. Functional recovery was assessed based on Sciatic Functional Index (SFI). Also, tracing motor neurons and histological studies were performed to evaluate nerve repair. The obtained data were analyzed by ANOVA test.
Results: The Mean±SD SFI value significantly increased in the muscle graft+NGF+laminin (-76.6±2.9) and muscle graft (-82.1±3.5) groups 60 days after the injury compared to the control group. The Mean±SD number of labeled motor neurons significantly increased in the muscle graft+NGF+laminin (78.6±3.1) and muscle graft (61.3±6.1) groups compared to the control group (P<0.001). The mean number of myelinated axons in the distal segments of the muscle graft+NGF+laminin increased significantly compared to the muscle graft group.
Conclusion: These findings suggest that muscle graft followed by NGF and laminin administration have therapeutic effects on nerve repair.
Introduction: Clavulanic acid (CLAV) is structurally similar to ceftriaxone, a potent stimulator of glial GlutamateTransporter-1 (GLT-1) expression. The present study aims at exploring the anti-nociceptive effects of CLAV, a beta-lactamase inhibitor in rats underwent sciatic nerve Chronic Constriction Injury (CCI).
Methods: CLAV (12.5, 25, 50 mg/kg) was administered intraperitoneally after the surgery for 14 consecutive days. Behavioral pain parameters were evaluated before and 3, 5, 7, 10 and 14 days after injury. Spinal GLT-1 level was measured via western blotting at days 7 and 14.
Results: CCI led to mechanical allodynia, cold allodynia and thermal hyperalgesia which started on postoperative days 3 and continued until the end of study. We found that CLAV (12.5 and 25 mg/kg) significantly attenuated all pain related behaviors as compared to the CCI animals treated with normal saline. Protein level of GLT-1 was down-regulated on day 14 following CCI and this phenomenon was reversed by fourteen days treatment of CLAV at the low doses of 12.5 and 25 mg/kg.
Conclusion: These results suggest that CLAV might provide a new therapeutic strategy for neuropathic pain and its effect might be partially associated with the up-regulation of GLT-1.
Introduction: In the elderly, functional balance, fear of falling, and independence in daily living activities are interrelated; however, this relationship may change under the influence of drug phase and the severity of disease in individuals with idiopathic Parkinson disease. This study aimed to investigate the association of functional balance, fear of falling, and independence in the Activities of Daily Living (ADL) with the drug on- and drug off-phases.
Methods: A total of 140 patients with Parkinson disease (age: Mean±SD; 60.51±12.32 y) were evaluated in terms of their functional balance, fear of falling, and independence in their daily activities by the Berg Balance Scale (BBS), Fall Efficacy Scale-International (FES-I), and Unified Parkinson Disease Rating Scale-ADL (UPDRS-ADL), respectively, in drug on- and drug off-phases. The Hoehn and Yahr scale recorded global disease rating. The Spearman coefficient, Kruskal-Wallis, and Mann-Whitney tests were used to find out whether the distribution of scale scores differs with regard to functional balance or disease severity.
Results: A strong correlation was found between the functional balance, fear of falling, and independence in ADL with both drug phases. The results also showed the significant difference in the distribution of the FES-I and UPDRS-ADL scores with regard to functional balance (except independence in ADL in drug off-phase). Also, the distribution of the scores of BBS, FES-I, and UPDRS-ADL showed significant differences with regard to disease severity.
Conclusion: The study showed a strong correlation between functional balance, fear of falling, and independence in ADL that can be affected by the drug phase and severity of the disease. However, more studies are needed to understand this relationship precisely.
Introduction: Migraine is a severe kind of headache with the chance hereditary of 50%. Molecular studies can promote understanding of migraine pathophysiology. One of which is bioinformatics approach that could provide additional information related to the identified biomarkers.
Methods: In this research, migraine genes are studies in terms of interaction pattern to introduce important individuals. Through STRING database Plug-in in Cytoscape, candidate genes for migraine were retrieved and analyzed by related applications. Based on centrality and action types (expression, activation, and inhibition) genes were screened.
Results: Numbers of 33 central genes including seven hub-bottlenecks were identified which 70% of central genes were involved in expression action with each other. Activation was dominate action relative to inhibition between the central genes.
Conclusion: The finding indicates that insulin is the most important gene relative to migraine. It seems regulation of metabolism play critical role in control of migraine.
Introduction: Orexin-containing neurons exist in the lateral hypothalamic region, sending their projections toward mesolimbic regions such as the Ventral Tegmental Area (VTA).
Methods: In the current study, a Reinstatement model is used to examine the effects of intra-VTA administration of SB334867 as an Orexin-1 Receptor (OX1R) antagonist on drug priming- and Forced Swim Stress (FSS)-induced reinstatement of morphine. Eighty-eight male adult albino Wistar rats, weighing 200-280 g, were bilaterally implanted by cannulas into the VTA. We induced the Conditioned Place Preference (CPP) by Subcutaneous (SC) injection of morphine (5 mg/kg) daily in three days. Then, the CPP score was calculated. After a 24-h “off” period following achievement of extinction criterion, the rats were tested for drug priming-induced reinstatement by a priming dose of morphine (1 mg/kg, SC) and for FSS-induced reinstatement 10 min after FSS. In the next experiments, the animals received different doses of intra-VTA administration of SB334867 (0.3, 3, and 1 nM/0.3 µL 12% DMSO per side) and bilaterally were subsequently tested for FSS- and morphine priming-induced reinstatement.
Results: Our findings indicated that the FSS could induce the reinstatement of seeking behaviors. Furthermore, intra-VTA administration of OX1R antagonists suppressed FSS- and drug priming-induced reinstatement dose-dependently.
Conclusion: It is concluded that FSS and drug priming-induced reinstatement might be mediated, at least in part, by stimulation of orexin receptors in the VTA.
Introduction: Neurogenesis mainly occurs in the hippocampus that is sensitive to radiation. More histological changes are reported at higher doses of radiation, while low dose radiation causes cognitive dysfunction in adult mammals. In the present study, we tried to correlate the Endoplasmic Reticulum (ER) stress-mediated hippocampus dysfunction after whole-body gamma radiation of mice.
Methods: Mice were exposed to a series of gamma radiations, followed by isolation of hippocampus. To elucidate the gene expression profile, qPCR was performed for ER stress markers CHOP, BiP, and hippocampal specific genes WFS1, Nectin 3, and Sostdc 1 on the isolated hippocampus. Expression of CHOP and ERK½ were analyzed by western blot on exposure to gamma radiation.
Results: qPCR results showed a significant increase in the expression of ER stress-specific genes CHOP, BiP, and decrease in hippocampal specific genes WFS1, Nectin3, and Sostdc1. Western blot study suggests a significant increase in ER stress proteins like CHOP and ERK½ expression.
Conclusion: Exposure to gamma radiation significantly increased the expression of ER-stress genes, suggesting that ER stress plays a major role in inducing radiation mediated dysfunction of the hippocampus. Also, significant downregulation of WFS1, Nectin3, and Sostdc1 genes suggests radiation mediated effect of hippocampal CA 1, CA 2, and CA 3 regions. A further significant increase of ERK½ shows involvement of the ERK pathway in mediating radiation-induced ER stress dysfunction in mice hippocampus. The present findings may lead to the identification of ER stress as a new marker to study radiation-induced neurodegenerative disorder.
Introduction: We investigated the sexually dimorphic effects of Dextromethorphan (DM) on cognitive and depression-like behaviors as well as on hippocampal histology in rats following acute administration.
Methods: Wistar rats of both sexes were treated with 25 or 50 mg/kg of DM for 7 days via intraperitoneal injection. At the end of the administration, behavioral studies were performed on the Tail Suspension Test (TST) for depressive-like behaviors and the Y-maze for cognitive behaviors. The rats’ brains were excised and processed for routine histological analysis.
Results: Our results showed that DM significantly increased (P<0.05) immobility time in the TST in male rats but not female ones, and decreased percentage alternation (P<0.001) on the Y-maze in both male and female rats. Histological analysis revealed no morphological changes in the hippocampus following DM treatment.
Conclusion: DM impairs cognitive functions in both male and female rats without histologic defects in the hippocampus. However, the induced depressive-like behaviors following DM administration may be sexually dependent.
Introduction: Pain is valuable in diagnosis and also warning of the patients. Many molecular reagents are introduced which are related to pain. In this research, the pain-related genes are screened to identify the critical ones.
Methods: First, the pain-related genes were pulling out from the STRING database, and Cytoscape software was used to make the interactome unit. Then the central genes and their neighbors were analyzed. Finally, the genes were clustered, and the essential genes were introduced.
Results: After analyzing 159 genes of the network, FOS, IL6, TNF, TAC1, IL8, and KNG1 were identified as the essential genes. Further analysis revealed that 88 genes are directly connected to the central genes. More resolution led to ignoring TNF and IL8 and considering SCN-alpha and PAICS as additional critical nodes.
Conclusion: Six critical genes related to pain were identified. They can be potentially considered as new drug targets. Further investigation is required to introduce the central genes as a pain killer.