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Background: Teucrium orientale is commonly used as an analgesic, antibacterial, antifungal, and antioxidant, protecting the liver and digestive system, and treating type 2 diabetes. Purpose: Evaluation of anti-nociceptive and anti-inflammatory properties of ethanolic plant extract using animal models. Methods: The ethanolic extract was prepared using the maceration method from grounddried aerial parts of the plant. Analgesic effects were determined by acetic acid-induced writhing and hot plate test on mice. The anti-inflammatory effect was evaluated using Carageenan and Cotton pellet tests on rats. Result: In the writhing test, TOE (100, 200 and 400 mg/kg) caused a significant reduction in abdominal contractions. Inhibition percentages of abdominal contractions in test groups (100, 200 and 400 mg/kg), morphine and mefenamic acid were 87.40%, 91.80%, 98.29%, 94.40% and 96.89%, respectively, which indicate the visceral analgesic effects. In hot plate tests, the pain threshold significantly increased in test groups. Extract in the doses of 100mg/kg (P< 0.001), 200mg/kg (P< 0.0001) and 400mg/kg (P< 0.001) significantly reduced the paw edema in the carrageenan test at the second hour. In the cotton pellet test, the prescribed doses of the plant (100-200 mg/kg; P<0.0001) significantly reduced the formation of granuloma tissue and reduced the rate of edema. The percentage of inhibition of granuloma tissue by indomethacin and extract at doses of 100 and 200 mg/kg were 39.19%, 66.75% and 75.49%, respectively, and the percentage of inhibition of exudates were 26.5%, 55.57% and 67.24%, respectively. Conclusion: These results clearly showed the anti-nociceptive and anti-inflammatory effect of Teucrium orientale extract in animal models. [ABSTRACT FROM AUTHOR]

Objective(s): Quercus brantii galls (QBGs) are well-known in Iranian traditional medicine for treating various diseases. The aim of study was to assess the acute and repeated oral toxicity of the hydroalcoholic extract of QBG in female rats. Materials and Methods: The ethanolic extract of QBG was administered in rats by gavage in both acute and repeated dose models. In the acute section of the study, a single oral dose of 2000 mg/kg was administered to female rat which were observed for physical symptoms and behavioral changes for 14 days. In the repeated dose toxicity study, the QBG extract (50, 500, and 1000 mg/kg/day) was administered for a period of 28 days to rats. On 28th day of experiment, blood sampling of animals was done for hematological and biochemical analysis and then sacrificed for histopathological examination of the harvested tissues (liver, heart, kidney, lung, spleen, stomach, ovary and uterus). Results: A single oral administration of the QBG extract (2000 mg/kg) did not produce mortality or significant behavioral changes during 14 days of observation. In repeated oral toxicity models, the extract significantly increased (P<0.05) the levels of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thyroid-stimulating hormone (TSH) and significantly decreased the levels of triiodothyronine (T3) and thyroxin (T4) in 500 and 1000 mg/kg dosage. The histopathological studies showed the absence of toxic effects of QBG (50 mg/kg dosage) and revealed evidence of microscopic lesions in the liver, kidney, stomach, heart, spleen, lung, uterus, and ovary in the 500- and 1000-mg/kg groups. Conclusion: The results indicate that the oral acute toxicity of QBG extract was of a low order with LD50 being more than 2000 mg/kg in rats. In addition, slight tissue damage was observed in some tissues in the 500 and 1000 mg/kg groups. It was found that prolonged use at higher doses i.e. 500 mg/kg/day of QBG extract should be avoided. [ABSTRACT FROM AUTHOR]

Dopaminergic pathways from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) play a critical role in reward-related phenomena as well as in the reinstatement of drug-seeking behavior. Stress is a major trigger for inducing reinstatement, however, the interaction between stress and the dopaminergic system is not well known. The present study was undertaken to investigate the effect of D1- and D2-like dopamine receptors within the NAc in forced swim stress (FSS)- and priming-induced reinstatement of morphine-seeking behaviors. The conditioned place preference (CPP) was induced by injecting morphine (5 mg/kg, SC for 3 days) and lasted for eight days after cessation of the morphine treatment. The FSS (6 min) and effective priming dose of morphine (1 mg/kg, sc) reinstated the extinguished morphine-induced CPP. In order to investigate the effect of intra-accumbal injection of SCH23390 as a D1-like receptor antagonist, or Sulpiride as a D2-like receptor antagonist on the FSS-induced reinstatement of morphine extinguished rats, animals received bilaterally intra-NAc injection of SCH23390 or Sulpiride (0.25, 1 and 4 μg/side) before application of FSS, and then, they were tested in the reinstatement day. Our results showed that the intra-accumbal administration of D1- and D2-like receptors antagonists dose-dependently blocked the effect of FSS on the reinstatement and significantly modulated morphine priming-induced reinstatement as well. These findings suggested that the D1- and D2-like dopamine receptors in the NAc involve in morphine-seeking behaviors and antagonism of these receptors can reduce the effect of stress on rewarding properties of morphine. [ABSTRACT FROM AUTHOR]

Objective(s): Pycnocycla bashagardiana is an endemic species found only in Iran. Due to the presence of myristicin as the major component of the fruit's oil we were prompted to assess the antinociceptive and anti-inflammatory properties of P. bashagardiana fruit's essential oil (PBFEO). Materials and Methods: The analgesic activities of PBFEO (100, 200, and 400 mg/kg, IP) were studied by hot-plate and formalin tests in mice. Control and standard groups received vehicle and morphine (5 mg/kg, IP), respectively. The acute anti-inflammatory effect of PBFEO (200 and 400 mg/kg, IP) were assessed by carrageenan-induced paw edema method in 30 min, 1, 2, 3, and 4 hr after carrageenan injection and the chronic anti-inflammatory effect of PBFEO (50 and 100 mg/kg, IP) were assessed by the cotton pellet-induced granuloma method in rats. Results: In hot-plate and formalin tests, the studied doses of PBFEO were not effective. However, in carrageenan test, all studied doses of PBFEO significantly reduced the paw edema in comparison to the control animals (P<0.05). Anti-inflammatory activity of PBFEO (200 and 400 mg/kg, P<0.05) was found to be more than mefenamic acid (30 mg/kg). In cotton pellet-induced granuloma, PBFEO was also effective regarding the transudate and granuloma formation amount. PBFEO was analyzed by gas chromatography-mass spectrometry and 12 constituents, representing 96.0% of the oil, were identified. The major component of the oil was characterized as myristicin which might be responsible for the antiinflammatory activity. Conclusion: The results suggest that PBFEO possesses biologically active constituents that have significant peripheral anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

• The orexin system is involved in METH-seeking behaviors by interacting with the orexin-2 receptors in theVTA. • Blockade of VTA orexin-2 receptors over the extinction period significantly decreased mean extinction latency. • Blockade of orexin-2 receptors in the VTA on reinstatement day prevented METH-induced CPP relapse. Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 μl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency. [ABSTRACT FROM AUTHOR]

Orexin plays a key role in mediating stress-induced drug relapse. However, the role of different types of orexinergic receptors that modulate stress-induced drug seeking remains unknown. The nucleus accumbens (NAc) has an important role in the reward system and receives orexinergic projections of the lateral hypothalamus. In addition, orexin interacts with other receptors that are involved in drug reinstatement. Therefore, in the present study, the role of orexin receptors in the NAc in morphine priming- induced reinstatement and the effect of food deprivation (FD) on drug reinstatement were examined. The extinguished morphine preference rats were tested for reinstatement following the 24-h FD condition after conditioning was induced. In the other groups, the animals were given intra-accumbal administration of SB334867 (01, 1 and 10 nM/0.5 μl DMSO) as an orexin-1 receptor antagonist and TCSOX229 (1, 5 and 25 nM/0.5 μl DMSO), as an orexin-2 receptor antagonist. The results showed that the blockade of two types of orexin receptors in the NAc remarkably attenuated the effect of FD on the drug reinstatement; however, they were more effective in FD condition. These findings indicate that the NAc is a brain area within which orexin has a fundamental role in the effect of stress on morphine-induced reinstatement and the effect of food deprivation- on the reinstatement of morphine. [ABSTRACT FROM AUTHOR]

It has been declared that dopamine receptors within the hippocampal formation are involved in emotion, memory, and pain processing. Remarkably, both CA1 and dentate gyrus (DG) areas of the hippocampal formation are involved in persistent peripheral nociceptive perception. A prior study showed that dopamine receptors within the hippocampal DG have a critical role in antinociception induced by forced swim stress (FSS), as a physical stressor, in the presence of formalin irritation. The present experiments were designed to assess whether dopaminergic receptors within the CA1 have any role in antinociceptive responses induced by restraint stress (RS) as a psychological stressor after applying the formalin test as an animal model of persistent inflammatory pain. The D1- and D2-like dopamine receptor antagonists, SCH23390 and Sulpiride (0.25, 1, and 4 μg/0.5 μl), were injected into the CA1 areas of ninety-six male albino Wistar rats 5 min before a 3-h period of restraint stress. Ten min after stress termination, a 50-μl formalin 2.5 % was subcutaneously injected into the plantar surface of the rat's hind paw to induce persistent inflammatory pain. Nociceptive behaviors in both phases of the formalin test were analyzed in the 5-min blocks for a 60-min period. The obtained results demonstrate that although RS could induce an antinociceptive response in both phases of the formalin test, microinjection of D1- and D2-like dopamine receptors, antagonists attenuated RS-induced analgesia. These results support the hypothesis that acute restraint stress could induce analgesia via dopaminergic projection to the CA1 region of the hippocampal formation. • Restraint stress decreased the pain-related behaviors in formalin-induced biphasic responses. • The RS-induced analgesia was significantly decreased by the blockade of D1- or D2-like DA receptors within the CA1. • The inhibitory effect of intra-CA1 Sulpiride on RS-induced analgesia was stronger than that of SCH23390 in both phases. • The role of both DA receptors within the CA1 in RS-induced analgesia was prominent in the early phase. [ABSTRACT FROM AUTHOR]

• Intra-ICV injection of cannabidiol during acquisition and expression decreased the METH-induced CPP. • Intra-CA1 injection of sulpiride reversed the effect of cannabidiol on the acquisition and expression of METH-induced CPP. • Cannabidiol prevented the METH-induced CPP through interaction with D2-like dopamine receptors in the CA1 region. • Role of hippocampal D2-like dopamine receptor in the effect of cannabidiol on expression of METH-induced CPP was predominant. • Intra-CA1 injection of sulpiride in the absence of cannabidiol had no effect on the METH-induced CPP. The main problem with addiction is a relapse with a high rate in methamphetamine (METH) abusers. Using addictive drugs repetitively will cause the reward. METH reward is due to an increase in dopamine levels, and the endocannabinoid system (ECS) has a modulatory role in reward through CB1 receptors. On the other hand, the hippocampus plays an important role in learning and memory, so it is involved in the neuroplasticity caused by METH abuse. Cannabidiol (CBD) has been shown to reduce the effects of METH through different mechanisms such as increasing the ECS activity, regulating emotional memory in the ventral hippocampus through D2-like dopamine receptors, and decreasing the mesolimbic dopaminergic activity. The present study tried to find out the role of hippocampal CA1 D2-like dopamine receptors (D2R) in the effects of cannabidiol on the acquisition and expression of METH-induced conditioned place preference (METH-CPP) in rats by using microinjection of sulpiride as a D2R antagonist. For this purpose, different groups of animals received different doses of sulpiride (0.25, 1, and 4 μg/0.5 μL DMSO; CA1), once prior to the injection of CBD (10 μg/5 μL for acquisition and 50 μg/5 μL for expression; ICV) and once in the absence of CBD. Control groups were also considered. In brief, findings showed that cannabidiol decreases METH-induced CPP. Intra-CA1 administration of sulpiride reversed the decreasing effects of cannabidiol on METH-induced CPP in both acquisition and expression phases but more prominent in the expression phase. The results showed that sulpiride did not affect the METH-induced CPP in the absence of cannabidiol. In conclusion, this study demonstrated that cannabidiol decreased METH-induced CPP in part through interaction with hippocampal CA1 D2-dopamine receptors. [ABSTRACT FROM AUTHOR]

• Injection of SB334867 into the DG dose-dependently blocked the antinociception induced by LH stimulation. • Injection of TCS OX2 29 into the DG dose-dependently blocked the antinociception induced by LH stimulation. • The role of intra-DG OX1 and OX2 receptors was somewhat equal in early and late phases of formalin nociception. • The contribution of OX1 receptor was more than that of the OX2 receptor to the LH stimulation-induced antinociception. Pain is a complex experience consisting of sensory, affective-motivational, and cognitive dimensions. Hence, identifying the multiple neural pathways subserving these functional aspects is a valuable task. The role of dentate gyrus (DG) as a relay station of neocortical afferents in the hippocampal formation (HF) in persistent pain is still controversial. The lateral hypothalamus (LH)-HF neural circuits are involved in numerous situations such as anxiety-like behavior, reward processing, feeding, orofacial as well as acute pain. Nonetheless, to our knowledge, the involvement of the LH-DG neural circuit in persistent pain has already remained unexplored. Adult male Wistar rats weighing 220–250 g were undergone stereotaxic surgery for unilateral implantation of two separate cannulae into the LH and DG. Intra-DG administration of the orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists, SB334867 and TCS OX2 29, respectively, was performed 5 min before intra-LH microinjection of carbachol. Animals were then undergone the formalin test using 50 μl formalin injection (2.5%) into the plantar surface of the hind paw. Microinjection of SB334867 or TCS OX2 29 into the DG region attenuated the antinociceptive effect produced by carbachol microinjection into the LH. The preventive effect of SB334867 and TCS OX2 29 on intra-LH carbachol-induced antinociception was approximately equal in both early and late phases of formalin nociception. The results suggest a neural pathway from the LH to the DG, which contributes to the modulation of formalin-induced inflammatory pain through the recruitment of OX1 and OX2 receptors within the DG. [ABSTRACT FROM AUTHOR]

• Intra-NAc administration of SB-334867 decreased sensitization to morphine in a dose-dependent manner. • Intra-NAc administration of TCS OX2-29 reduced sensitization only at the highest dose. • The role of the OX1r within the NAc was more prominent than that of OX2r in sensitization to morphine. It has been reported that orexins A and B are involved in the mediation of drug reward. In addition, the nucleus accumbens (NAc) has an important role in the development of morphine-conditioned place preference (CPP) and morphine sensitization. In the present study, we aimed to evaluate the role of orexin receptors within the NAc in morphine sensitization using CPP paradigm. Adult male Wistar rats were used and were bilaterally implanted by two cannulae in the NAc. The animals received intra-accumbal administration of OX1 or OX2 receptor antagonists, SB-334867 (0.1, 1, and 10 nM/side) or TCS OX2 29 (2, 10, and 20 nM/side), 10 min before morphine injection during the sensitization period, during which the animals received repeated administration of morphine (5 mg/kg; s.c.) once daily for three days followed by 5 morphine injection-free days. Then the CPP paradigm was conducted for the evaluation of morphine rewarding properties by injecting a sub-threshold dose of morphine (0.5 mg/kg; s.c.). The results showed that bilateral administration of OX1 receptor antagonist into the NAc reduced acquisition of morphine sensitization in a dose-dependent manner, but OX2 receptor antagonist produced similar effect only at its highest dose, indicating that OX1 and OX2 receptors within the NAc are involved in the acquisition of morphine sensitization. [ABSTRACT FROM AUTHOR]

• Force swimming stress decreased pain-related behaviors in acute model of pain. • OX1 and OX2 receptors antagonist in DG, decreased stress induced analgesia. • Role of both receptors was the same in modulating stress-induced analgesia. Studies establish that the brain's Orexin system is involved in pain modulation. Orexin-1 and orexin-2 receptors (OX1 and OX2r, respectively) are essential in responsiveness to stressful stimuli. Some evidence indicates that the hippocampus's dentate gyrus (DG) potentially modulates pain and stress. The present study examined the involvement of OX1 and OX2 receptors within the DG in response to acute pain after exposure to forced swim stress (FSS). Five to seven days post-stereotaxic surgery, the baseline tail-flick latency (TFL) was taken from the animal, then rats unilaterally received through an implanted cannula either different doses of OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), OX2r antagonist (TCS OX2 29; 1, 3, 10 and 30 nmol), or vehicle (0.5 μl solution of 12% DMSO). After 5 min, rats were exposed to the FSS for six minutes. Subsequently, the tail-flick test was conducted, and the TFLs were measured at the 60-min time set intervals. Results indicated that FSS produces antinociceptive responses in the tail-flick test. Two-way ANOVA analysis showed that Microinjection of OX1r and OX2r antagonists into the DG region of the brain reduced FSS-induced analgesia in the tail-flick test. The decrement effects of these two antagonists were almost the same. Additionally, results showed that the role of both receptors was the same in modulating stress-induced analgesia (SIA). These findings show that the orexin system in the hippocampal DG region might be partially involved in the SIA in acute pain. [ABSTRACT FROM AUTHOR]

Background: Mentha mozaffarianii, an endemic species from the Labiatae family, is used in Iranian traditional medicine. This study evaluated the acute and repeated oral toxicity of the Mentha mozaffarianii essential oil (MMEO) in rats and mice. Methods: To assess the toxicity profile of the MMEO, we administered the essential oil to 48 rats and mice of both sexes by gavage in acute and repeated models. In acute toxicity, the animals were administered the MMEO (2000 mg/kg) and were monitored for 14 days. In the repeated toxicity, the MMEO was administered (100 mg/kg) daily for 4 weeks. On the 28th day, all the animals were scarified and blood and tissue samples were prepared. All the clinical, biochemical, and histopathological changes were assessed and compared with those in the controls. Statistical significance was determined by one- and two-way analyses of variance, followed by the Tukey test using GraphPad Prism 6. Results: In the acute test, there was no mortality; therefore, the oral LD50 value determined in the mice and rats of both sexes was greater than 2000 mg/kg. In the repeated test, the animals received the MMEO and there was no mortality. In the biochemical analysis, there were significant increases in blood glucose, cholesterol, ALT, AST, ALP, and TSH in the female rats and also in BUN in the male rats. The histopathological studies revealed evidence of microscopic lesions in the liver, kidney, stomach, and small intestine tissues of the MMEO group. Conclusion: The results indicated that the acute toxicity of the MMEO in the mice and rats was of a low order and it revealed slight tissue damage to several organs when given subchronically at a dose of 100 mg/kg. [ABSTRACT FROM AUTHOR]

• Exposure to forced swim stress induced analgesic responses in both phases of formalin test. • Intra-CA1 injection of OX1r and OX2r antagonists attenuated stress-induced analgesia in the formalin test. • The contribution of CA1 hippocampal OX1r and OX2r in the SIA was more predominant in the early phase. • TCS OX2 29 as the OX2r antagonist is more potent than SB334867 as the OX1r antagonist in both phases of the formalin test. Stress activates multiple neural pathways and neurotransmitters that often suppress pain perception, the phenomenon called stress-induced analgesia (SIA). Orexin neurons from the lateral hypothalamus project to entire brain structures such as the hippocampus. The present study examined this hypothesis that orexinergic receptors in the CA1 region of the hippocampus may play a modulatory role in the development of SIA in formalin test as an animal model of persistent inflammatory pain. One hundred-two adult male Wistar rats were administered with intra-CA1 orexin-1 receptor (OX1r) antagonist, SB334867, at the doses of 3, 10, 30, and 100 nmol or TCS OX2 29 as orexin-2 receptor (OX2r) antagonist at the doses of 1, 3, 10, and 30 nmol. Five min later, rats were exposed to forced swim stress (FSS) for a 6-min period. Then, pain-related behaviors induced by formalin injection were measured at the 5-min blocks during a 60-min period of formalin test. The current study indicated that solely stress exposure elicits antinociception in the early and late phases of the formalin test. The FSS-induced analgesia was prevented by intra-CA1 administration of SB334867 or TCS OX2 29 during either phase of the formalin test. Moreover, the contribution of the OX2r in the mediation of analgesic effect of stress was more prominent than that of the OX1r during both phases of the formalin test. It is suggested that OX1r and OX2r in the CA1 region of the hippocampus are involved in stress-induced analgesia in the animal model of persistent inflammatory pain. [ABSTRACT FROM AUTHOR]

• ICV administration of cannabidiol prevented the acquisition of MET-induced conditioned place preference. • Cannabidiol dose-dependently reduced the expression of methamphetamine-induced CPP. • The inhibitory effect of CBD was more powerful in the acquisition than that in the expression phase. • Neither CBD nor MET changed locomotion activity during MET-induced CPP in the rats. Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 μg/5 μL DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 μg/5 μL) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 μg/5 μL) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed. [ABSTRACT FROM AUTHOR]