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Thymoquinone (TQ) is the main biologically active substance of Nigella sativa (black seeds). It has anti-cancer, anti-inflammatory, anti-diabetic, anti-oxidative and anti-nociceptive properties. This study was aimed to explore the effect of TQ on acetic acid-induced visceral nociception. The central mechanisms of the effect of TQ were investigated using cannabinergic (AM251) and α2-adrenergic (yohimbine [Yoh]) antagonists. The lateral ventricle of the brain was cannulated for intracerebroventricular (ICV) injections. Visceral nociception was induced by intra-peritoneal (IP) injection of acetic acid (1.00% in a volume of 1.00 mL). Measuring the latency time to the first writhing appearance and counting the number of writhing in 5-min intervals for a period of 60 min were performed. Locomotor activity was determined using an open-field test. Oral administration (PO) of 2.50 and 10.00 mg kg-1 TQ increased the latency time to the first writhing appearance and decreased the number of writhing. The AM251 (5.00 µg per rat; ICV) and Yoh (5.00 µg per rat; ICV) partially prevented TQ (10.00 mg kg-1; PO)-induced anti-nociception. Locomotor activity was not altered by these treatments. The results of the present study showed that TQ had the ability to reduce visceral nociception caused by IP injection of acetic acid. The central mechanisms of this action of TQ might be partially mediated by cannabinergic and α2-adrenegic receptors.
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INTRODUCTION: Ventral Tegmental Area (VTA) is a core region of the brainstem that contributes to different vital bio-responses such as pain and addiction. The Dopaminergic (DA) cellular content of VTA has major roles in different functions. This study aims to evaluate the cellular effect of tramadol on the putative VTA-DA neurons. METHODS: Wistar rats were assigned into three groups of control, sham, and tramadol-treated. The animals were anesthetized and their VTA-DA neuronal activity was obtained under controlled stereotaxic operation. The firing rate of the neurons was extracted according to principal component analysis by Igor Pro software and analyzed statistically considering P<0.05 as significant. Tramadol (20 mg/kg) was infused intraperitoneally. RESULTS: Overall, 121 putative VTA-DA neurons were isolated from all groups. In tramadol-treated rats, the inhibition of the neuronal firing was proposed as tolerance and the excitation period as dependence or withdrawal. The Mean±SD inhibition time lasted up to 50.34±10.17 minutes and 31% of neurons stopped firing and silenced after 24±3 min on average but the remaining neurons lowered their firing up to 43% to 67% of their baseline firing. All neurons showed the excitation period, lasted about 56.12±15.30 min, and the firing of neurons increased from 176% to 244% of their baseline or pre-injection period. CONCLUSION: The tolerance and dependence effects of tramadol are related to the changes in the neuronal firing rate at the putative VTA-DA neurons. The acute injection of tramadol can initiate neuroadaptation on the opioid and non-opioid neurotransmission to mediate these effects.
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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.
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INTRODUCTION: Inflammatory pain is a common sign of chronic diseases. Some brain regions such as locus coeruleus (LC) of the brainstem nor-epinephrine (NE) system have a key role in The mechanisms of the pain modulation and dependence. Bupropion synthesized as an antidepressant, but it is using for smoke cessation. It can change morphine withdrawal signs such as pain related behaviors. This study tested the acute effect of intra-LC microinfusion of bupropion on the formalin-induced pain behavior in rats. METHODS: Wistar male rats were divided into 6 groups (control-naïve, control-operated, shamoperated, and 3 treated groups with 10(-2), 10(-3), 10(-4) mol/µl intra-LC of bupropion). The injection guide cannulae were implanted into LC nuclei bilaterally by stereotaxic coordinated surgery under sterile condition. The sham group received normal saline as drug vehicle but control groups had no intra-LC injections. Formalin (50 µl, 2.5%) was injected subcutaneously in plantar region of the right hindpaw in all animals (30 min after drug administration in treated animals). Nociceptive signs were observed continuously and registered on-line each minute. Common pain scoring was used for pain assessment. RESULTS: The analysis of data by one-way ANOVA showed that bupropion can reduce pain behavior scores significantly. Bupropion reduced total pain score in the phase 01 (60%) and phase 02 (52%) of maximal behavior compared to the sham group, dose dependently and significantly. The pain scores of controls and sham groups had no significant difference. DISCUSSION: The results showed that bupropion has analgesic effects on LC neurons and can alter the neurochemical involvement of LC in pain process. Bupropion has different and significant effect on early and late phases of formalin test.
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INTRODUCTION: The most common interpretation for the mechanisms of antidepression is the increase of the brain monoamine levels such as dopamine (DA). The increase of DA can reduce depression but it can also decrease the monoamine release because of autoreceptor inhibition. Although bupropion can decrease the dopamine release, there is evidence about stimulatory effects of chronic application of bupropion on ventral tegmental area (VTA) neurons. In this study, the intra-VTA acute microinfusion of bupropion on putative VTA non-Dopaminergic (VTA-nonDA) neuronal firing rates was evaluated by a single neuron recording technique. METHODS: Animals were divided into 7 groups (sham, and 6 bupropion-microinfused groups with 1, 10(-1), 10(-2), 10(-3), 10(-4), and 10(-5) mol, 1 µl/3 min, intra-VTA). A single neuron recording technique was done according to the stereotaxic coordination. After 10 min baseline recording, ACSF or bupropion was microinfused. The recording continued to recovery period in the treated groups. The prestimulus time (PST) and interspike interval (ISI) histograms were calculated for every single unit. The assessment of the drug effect was carried out by one-way analysis of variance (ANOVA) and Post-hoc test. RESULTS: 126 non-DA neurons were separated. Bupropion could inhibit 116 neurons and 11 neurons had no significant response. Maximum inhibition was 79.1% of baseline firing rate with 44.3 min duration. The inhibitory effect of bupropion was dose-dependent. DISCUSSION: The acute inhibitory effects of bupropion on VTA-nonDA neurons can explain the fast inhibitory effects of bupropion and other antidepressants on the VTA. These data can explain some side effects of antidepressants.
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BACKGROUND: The chronic pain can disturb physical, psychological, and social performances. Analgesic agents are widely used but some antidepressants (ADs) showed analgesia also. Bupropion is using for smoke cessation but it can change morphine withdrawal signs such as pain. This study tested the acute systemic effect of bupropion on formalin induced pain behavior in rats. METHODS: Wistar male healthy rats were divided into 7 groups (control, sham, and 5 treated groups with 10, 30, 90, 120, and 200 mg/kg of bupropion, i.p.). The bupropion injected 3 hours prior to formalin induced pain behavior. Formalin (50 µl, 2.5%) was injected subcutaneously in dorsal region of right hindpaw in all animals. Nociceptive signs were observed continuously on-line and off-line each minute. Common pain scoring was used for pain assessment. RESULTS: The analysis of data by one-way ANOVA showed that bupropion can reduce pain scores in the second phase but not in first phase. Bupropion decreased the licking/biting duration significantly in first and second phase of formalin test. CONCLUSIONS: The results showed that bupropion has analgesic effects at systemic application. The change of second phase of the pain behavior was significant and it revealed that central mechanisms involve in bupropion analgesia.