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The cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats.

Purpose: Paracetamol has been shown to exert anxiolytic-like effects mediated by endocannabinoids via cannabinoid CB1 receptors. Dipyrone is an analgesic with similar effects to paracetamol rather than non-steroidal anti-inflammatory drugs. Involvement of central structures to its effects are long under debate, whereas recent findings suggesting contribution of cannabinoid CB1 receptors to its antinociceptive effect support this argument. Taken together, the purpose of this study was to investigate whether dipyrone possesses anxiolytic-like behavior; contribution of cannabinoid CB1 and CB2 receptors and TRPV1 receptors will be determined in case of observing any effect of dipyrone in anxiety tests. Material and Methods: Balb-c mice effects of dipyrone (150, 300, 600 mg/kg, i.p.) were assessed in three-chamber social interaction, open-field, elevated plus-maze and rota rod tests. The cannabinoid CB1 antagonist AM251 (1 mg/kg i.p.), the CB2 antagonist SR 144528 (1 mg/kg i.p.) and the TRPV1 antagonist capsazepine (3 mg/kg i.p.) were going to be administered before dipyrone injections if any effect of dipyrone occurs. Results: Dipyrone had no effect at any dose in behavioral tests (three-chamber social interaction, open-field, elevated plus-maze and rota rod tests). Therefore, dipyrone is not tested together with the cannabinoid CB1 and CB2 antagonists and the TRPV1 receptor antagonist. Conclusion: Unlike paracetamol, dipyrone did not possess anxiolytic-like effects in mice. Discrepancies in experimental models and methodologies may be the reason of our results.

Non-steroidal anti-inflammatory drugs produce antinociceptive effects mainly through peripheral cyclooxygenase inhibition. In opposition to the classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone exert weak anti-inflammatory activity, their antinociceptive effects appearing to be mostly due to mechanisms other than peripheral cyclooxygenase inhibition. In this review, we classify classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone as “non-opioid analgesics” and discuss the mechanisms mediating participation of the endocannabinoid system in their antinociceptive effects. Non-opioid analgesics and their metabolites may activate cannabinoid receptors, as well as elevate endocannabinoid levels through different mechanisms: reduction of endocannabinoid degradation via fatty acid amide hydrolase and/or cyclooxygenase-2 inhibition, mobilization of arachidonic acid for the biosynthesis of endocannabinoids due to cyclooxygenase inhibition, inhibition of endocannabinoid cellular uptake directly or through the inhibition of nitric oxide synthase production, and induction of endocannabinoid release.

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action.

Objective: The effects of antipsychotic drugs, of whose different classes can be used in the treatment of patients with resistant to schizophrenia, on the fetus and the benefits of the treatment to the mother should be taken into consideration before making a decision about initiating treatment. This study aimed to examine the effects of prenatal exposure to various antipsychotic agents on learning and memory in adult rats.Method: In this study, antipsychotic drugs from different chemical classes (2 mg/kg haloperidol, 100 mg/kg thioridazine, 200 mg/kg sulpiride, 20 mg/kg chlorprothixene, 40 mg/kg clozapine, 10 mg/kg fluphenazine, 20 mg/kg chlorpromazine) and water for the control group were administered to pregnant Sprague-Dawley dams through gavage during the pregnancy period. In total, 16 groups were created and tested in the Morris water maze by dividing offspring of eight mother rats into male and female rat groups (n=10) on postpartum day 60. Learning was tested with hidden platform task and ...

BackgroundFor centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.ObjectiveThe goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.Material and methodsScratching behaviour was induced by intradermal injection of serotonin (50 µg/50 µl/mouse) to Balb/c mice. The neurotoxins 5,7-dihydroxytryptamine (5,7-DHT, 50 μg/mouse) and 6-hydroxydopamine (6-OHDA, 20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. WIN 55,212-2 (1, 3, 10 mg/kg, i.p.) dose-dependently attenuated serotonin-induced scratches. Neurotoxic destruction of neither the serotonergic nor the noradrenergic systems by 5,7-DHT and 6-OHDA, respectively, had any effect on the antipruritic action of WIN 55,212-2.ConclusionOur findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect.

Background Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing μ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice. Methods Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus. Results Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p

Glutamate is believed to be the predominant excitatory neurotransmitter in the networks responsible for itch-related behavior. Beta-lactam antibiotics were shown to exert neuroprotective effects by increasing expression of the glutamate transporter GLT-1. We observed whether repeated administration of the beta-lactam antibiotic ceftriaxone suppresses serotonin-induced itch-related behavior (similarly to its effect on pain transmission) in mice. Chronic, but not acute, ceftriaxone introductions reduced the number of serotonin-induced scratches; dihydrokainic acid, a selective GLT-1 transporter inhibitor, partly but significantly abolished this effect of ceftriaxone. Our findings suggest that GLT-1 activation by beta-lactam antibiotics looks promising for the treatment of chronic itch. Як вважають, глутамат є основним збуджуючим нейротрансмітером у нейронних мережах, відповідальних за поведінкові моторні прояви при почутті свербіжу. β-лактамні антибіотики мають нейропротективні властивості, оскільки забезпечують посилену експресію глутаматного транспортера GLT-1. Ми з’ясовували, чи здатне повторне введення β-лактамного антибіотика цефтриаксону пригнічувати викликані ін’єкціями серотоніну поведінкові моторні прояви (чухальні рухи), пов’язані з індукцією почуття свербіжу (подібно до впливу цього агента на біль) у мишей. Хронічні (але не поодинокі) введення цефтриаксону викликали зменшення кількості рухів чухання. Селективний блокатор транспортера GLT-1 дигідрокаїнова кислота частково, але істотно перешкоджала цьому ефекту цефтриаксону. Наші спостереження дають підстави вважати, що активація GLT-1 β-лактамними антибіотиками є перспективним підходом у лікуванні хронічного свербіжу.

Objective: The aim of the study was to determine the protective effect of curcumin against ionizing radiation-induced cataract in the lens of rats. Material and Methods: Rats were divided into six groups. Group 1: Control, Group 2: Dimethyl sulfoxide (DMSO), Group 3: DMSO+curcumin, Group 4: Irradiation, Group 5: Irradiation+DMSO, Group 6: Irradiation+DMSO+curcumin. A 15 Gy total dose was given to 4, 5, 6 groups for radiation damage. Curcumin (100 mg/kg) was dissolved in DMSO and given by intragastric intubation for 28 days. At the end of the experiment, lenses were graded and enucleated. The lenticular activity of the antioxidant enzymes, total antioxidant and glutathione peroxidase (GSH-Px), and the malondialdehyde (MDA) were measured. Results: 100% Cataract was seen in the irradiation group. Cataract rate fell to 40% and was limited at grade 1 and 2 in the curcumin group. In the irradiation group, antioxidant enzyme levels were decreased, MDA levels were increased. There was an increase in antioxidant enzyme levels and a significant decrease in MDA in the group which was given curcumin. Conclusion: Curcumin has antioxidant and radioprotective properties and is likely to be a valuable agent for protection against ionizing radiation. Hence, it may be used as an antioxidant and radioprotector against radiation-induced cataractogenesis. Turkish Başlık: Sıçanlarda İyonizan Radyasyonla Oluşturulan Katarakt Üzerine Curcuminin Koruyucu Etkisi Anahtar Kelimeler: Katarakt, curcumin, iyonizan radyasyon, lipid peroksidasyonu, oksidatif stres, radioprotektif Amaç: Çalışmamızın amacı, sıçan lenslerinde iyonizan radyasyonla oluşturulan katarakt modelinde curcuminin koruyucu etkisini incelemektir. Gereç ve Yöntemler: Sıçanlar altı gruba ayrıldı. Grup 1: Kontrol, Grup 2: Dimetil sülfoksid (DMSO), Grup 3: DMSO+curcumin, Grup 4: Radyasyon, Grup 5: Radyasyon+DMSO, Grup 6: Radyasyon+DMSO+curcumin. Grup 4, 5 ve 6'ya hasar oluşturmak için iyonizan radyasyon toplam 15 Gy dozunda verildi. Curcumin (100 mg/kg), DMSO içinde çözülerek 28 gün süresince intragastrik yoldan verildi. Çalışmanın sonunda, lensler sınıflandırıldı ve çıkarıldı. Lens dokusunda antioksidan durumu değerlendirmek üzere total antioksidan, glutatyon peroksidaz (GSH-Px) enzimleri ve oksidan durumu değerlendirmek üzere malondialdehit (MDA) düzeylerine bakıldı. Bulgular: Radyasyon alan grupta %100 katarakt görüldü. Curcumin verilen grupta bu oran %40'a düştü ve grade 1 ve 2 ile sınırlıydı. Radyasyon alan grupta, kontrol grubuna göre antioxidan enzim seviyesi düştü, MDA enzim seviyesi yükseldi. Curcumin verilen grupta radyasyon grubuna göre ise anlamlı şekilde antioxidan enzim seviyesi yükseldi, MDA enzim seviyesi düştü. Sonuç: Curcumin antioksidan ve radioprotektif özelliklere sahiptir ve iyonizan radyasyona karşı koruyucu olarak değerli bir ajan olması nedeni ile antioksidan ve radioprotektör olarak radyasyon nedenli katarakt oluşumunda kullanılması önerilebilir.

The response to opioids is reduced in neuropathic pain states. We examined the effect of the combination of morphine (0.1 mg/kg) and magnesium sulfate (125 mg/kg) on behavioral signs of neuropathic pain in spinal nerve ligated rats. Administered alone, neither drug produced any effect, but the combination exerted a significant anti-allodynic effect, which was partially reversed by naloxone. These results suggest that combining low doses of magnesium sulfate with opiates might be an alternative in treating neuropathic pain, with reduced risk of side effects.

We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES) in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4, and 4 mg/kg on day 5, twice daily, ip) to deplete mast cell contents. Morphine (0.001-10 mg/kg, ip; N = 20) produced a dose-dependent anticonvulsive effect against MES seizure in mice with non-depleted mast cells, whereas it did not exert any anticonvulsive effect in mice with depleted mast cells. These results indicate that morphine produces its anticonvulsive effect against maximal electroconvulsive shock in mice by liberating histamine from mast cells.

Morphine is known to release histamine from mast cells. It is also known that histamine receptors mediate some of morphine's effects on the central nervous system. The contribution of H1- and H2-receptors to the effect of morphine on maximal electroconvulsive shock in mice was investigated in the present experiments. Morphine showed a dose-dependent anticonvulsive effect, but produced spontaneous clonic convulsions at higher doses (100 mg/kg, i.p.). The anticonvulsive effect of morphine (1 mg/kg, i.p.) was antagonized by histamine H1-receptor antagonists, dimethindene (0.1 mg/kg, i.p.) promethazine (0.4 mg/kg, i.p.) and pheniramine (30 mg/kg, i.p.), and naloxone (10 mg/kg, i.p.), but not by the H2-receptor antagonist ranitidine (10-50 micrograms, i.c.v.). These results show that morphine has an anticonvulsive effect via histamine H1-receptors against maximal electroconvulsive shock in mice.

Morphine has long been known to have potent effects on body temperature. It has been suggested that both N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) pathway are involved in thermoregulation and also known to play important roles in some of morphine effects. The aim of this study was therefore to investigate the contribution of NMDA receptors and NO to the thermoregulatory effect of morphine. Morphine produced a hypothermic effect, especially at the dose of 10 mg/kg. Ketamine (5–40 mg/kg, i.p.) and NG-nitro-L-arginine-methyl ester (L-NAME, 1–100 mg/kg, i.p.) also produced hypothermic effects with their higher doses. At doses which themselves produced no effect on colonic temperature in mice, both ketamine (10 mg/kg, i.p.) and L-NAME (10 mg/kg, i.p.) enhanced the hypothermic effect of morphine (10 mg/kg, i.p.). These results further support the relationship between NO and NMDA receptors and suggest a possible role of NMDA-NO pathway in the thermoregulatory effect of morphine.