Magnetic Resonance Imaging and Manganism: A Narrative Review and Laboratory Recommendations.

In recent years, a series of articles has been published concerning magnetic resonance imaging (MRI) studies in a group of patients exposed to manganism, specifically factory workers, welders, and individuals with liver diseases, as well as those abusing home-produced ephedrone. Some potential symptoms of manganese toxicity include motor disturbances, neurocognitive problems, sleep disorders, and psychosocial changes. Despite various publications on MRI research in individuals with an elevated risk of manganism, there is a noticeable absence of a comprehensive review in this field. The detection of the accumulation of manganese in the brain through MRI can confirm the diagnosis and guide appropriate treatment. Due to the high cost of determining manganese ion levels in biological material, an additional aim of the manuscript was to identify simple medical laboratory parameters that, when performed concurrently with MRI, could assist in the diagnosis of manganism. Among these types of parameters are the levels of bilirubin, magnesium, liver enzymes, creatinine, hemoglobin, and hematocrit.

Procognitive, Anxiolytic, and Antidepressant-like Properties of Hyperoside and Protocatechuic Acid Corresponding with the Increase in Serum Serotonin Level after Prolonged Treatment in Mice.

Two polyphenols-hyperoside (HYP) and protocatechuic acid (PCA) were reported to exert antidepressant activity in rodents after acute treatment. Our previous study also showed that this activity might have been influenced by the monoaminergic system and the upregulation of the brain-derived neurotropic factor (BDNF) level. A very long-term pharmacological therapy is required for the treatment of a patient with depression. The repetitive use of antidepressants is recognized to impact the brain structures responsible for regulating both emotional and cognitive behaviors. Thus, we investigated the antidepressant, anxiolytic, and procognitive effects of HYP and PCA in mice after acute and prolonged treatment (14 days). Both polyphenols induced an anxiogenic-like effect after acute treatment, whereas an anxiolytic effect occurred after repetitive administration. PCA and HYP showed procognitive effects when they were administered acutely and chronically, but it seems that their influence on long-term memory was stronger than on short-term memory. In addition, the preset study showed that the dose of 7.5 mg/kg of PCA and HYP was effective in counteracting the effects of co-administered scopolamine in the long-term memory impairment model induced by scopolamine. Our experiments revealed the compounds have no affinity for 5-HT1A and 5-HT2A receptors, whereas a significant increase in serum serotonin level after prolonged administration of PCA and HYP at a dose of 3.75 mg/kg was observed. Thus, it supports the involvement of the serotonergic system in the polyphenol mechanisms. These findings led us to hypothesize that the polyphenols isolated from Impatiens glandulifera can hold promise in treating mental disorders with cognitive dysfunction. Consequently, extended studies are necessary to delve into their pharmacological profile.

New aryl-/heteroarylpiperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione: Synthesis and preliminary studies of biological activities.

Compounds containing dicarboximide skeleton such as succinimides, maleimides, glutarimides, and phthalimides possess broad biological properties including anti-fungal, antibacterial, antidepressant, or analgesic activities. The piperazine ring is found in a wide range of molecules that have demonstrated a variety of biological functions such as anticancer action and 5-HT receptors agonist/antagonist activity. In the present study, we combined both structures to develop new antitumor agents, a series of piperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione and evaluated their biological activity. The structures of all tested compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was assessed in vitro against eight human cancer cell lines, namely prostate (PC3), colon (HCT116, SW480, SW620), leukemia (K562), liver (HepG2), lung (A549) and breast (MDA-Mb-231) in contrast to normal HMEC-1 cell line, by using MTT and Trypan blue method. The tested compounds showed significant activity toward cancer cells. The most pronounced cytotoxic effect was observed in K562 and HCT116 with IC50 values below 10 µM for all studied compounds. Importantly, the most promising derivatives for each cancer cell line (IC50 < 10 µM) exerted a weaker cytotoxic effect toward normal HMEC-1 cells than cancer cells. The evaluation of proapoptotic and inhibitory effects on IL-6 release showed that K562 and HCT116 cells were more sensitive to studied compounds than other cancer cell lines. Furthermore, for all piperazine derivatives, the functional activities at the 5-HT1A, D2 receptors as well as their binding affinities at the 5-HT2A, H1 and M receptors, were determined. The current investigation was able to successfully design compounds with both serotoninergic and anticancer properties. It serves as a good starting point for a multimodal approach for the management of cancer and cancer-related symptoms.

Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring.

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a-c) and the corresponding acetylated derivatives was used (3a-c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a-c) and corresponding N-acetyl derivatives (3a-c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a-c and 3a-c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

Advanced Biomarkers of Hepatotoxicity in Psychiatry: A Narrative Review and Recommendations for New Psychoactive Substances.

One of the factors that increase the effectiveness of the pharmacotherapy used in patients abusing various types of new psychoactive substances (NPSs) is the proper functioning of the liver. However, the articles published to date on NPS hepatotoxicity only address non-specific hepatic parameters. The aim of this manuscript was to review three advanced markers of hepatotoxicity in psychiatry, namely, osteopontin (OPN), high-mobility group box 1 protein (HMGB1) and glutathione dehydrogenase (GDH, GLDH), and, on this basis, to identify recommendations that should be included in future studies in patients abusing NPSs. This will make it possible to determine whether NPSs do indeed have a hepatotoxic effect or whether other factors, such as additional substances taken or hepatitis C virus (HCV) infection, are responsible. NPS abusers are at particular risk of HCV infection, and for this reason, it is all the more important to determine what factors actually show a hepatotoxic effect in them.

Reasons, Form of Ingestion and Side Effects Associated with Consumption of Amanita muscaria.

In recent months, there has been a new trend involving the consumption of Amanita muscaria. The aim of this article was to investigate the reasons for consumption, the form taken and the adverse symptoms that were indicated by those consuming Amanita muscaria. After analysing 5600 comments, 684 people were included in the study, who, in social media groups such as Facebook, stated the purpose of consuming the mushroom (n = 250), the form of mushroom they were taking (n = 198) or the adverse symptoms they experienced (n = 236). The gender of the subjects differentiated the parameters analysed. In the study group of women, the main purpose of consuming Amanita muscaria was to reduce pain, as well as to reduce skin problems, while in men it was mainly to relieve stress, reduce the severity of depressive symptoms and reduce insomnia (p < 0.001). With regard to the form of mushroom ingested, tincture was predominant in the women's study group, while dried was predominant in the men (p < 0.001). In terms of side effects, women reported primarily headaches, while men reported nausea, vomiting, abdominal pain and drowsiness (p < 0.001). Advanced research on Amanita muscaria should be carried out to make the community aware of the toxicity of this fungus.

New Piperazine Derivatives of 6-Acetyl-7-hydroxy-4-methylcoumarin as 5-HT1A Receptor Agents.

A series of 15 new derivatives of 6-acetyl-7-hydroxy-4-methylcoumarin containing a piperazine group were designed with the help of computational methods and were synthesized to study their affinity for the serotonin 5-HT1A and 5-HT2A receptors. Among them, 6-acetyl-7-{4-[4-(3-bromophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one (4) and 6-acetyl-7-{4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one (7) exhibited excellent activity for 5-HT1A receptors with Ki values 0.78 (0.4-1.4) nM and 0.57 (0.2-1.3) nM, respectively, comparable to the Ki values of 8-OH-DPAT (0.25 (0.097-0.66) nM). The equilibrium dissociation constant values of the tested compounds showed differential intrinsic activities of the agonist and antagonist modes.

Identification of Novel CB2 Ligands through Virtual Screening and In Vitro Evaluation.

Cannabinoid receptor type 2 (CB2) is a very promising therapeutic target for a variety of potential indications. However, despite the existence of multiple high affinity CB2 ligands, none have yet been approved as a drug. Therefore, it would be beneficial to explore new chemotypes of CB2 ligands. The recent elucidation of CB2 tertiary structure allows for rational hit identification with structure-based (SB) methods. In this study, we established a virtual screening workflow based on SB techniques augmented with ligand-based ones, including molecular docking, MM-GBSA binding energy calculations, pharmacophore screening, and QSAR. We screened nearly 7 million drug-like, commercially available compounds. We selected 16 molecules for in vitro evaluation and identified two novel, selective CB2 antagonists with Ki values of 65 and 210 nM. Both compounds are structurally diverse from CB2 ligands known to date. The established virtual screening protocol may prove useful for hit identification for CB2 and similar molecular targets. The two novel CB2 ligands provide a desired starting point for future optimization and development of potential drugs.

Matrix metalloproteinase-3 serum levels in schizophrenic patients.

OBJECTIVES: It has been reported that matrix metalloproteinase, MMP-3 may play a significant role in the pathophysiology of mental disorders. However, there are no data on the level of MMP-3 in people suffering from schizophrenia, or its influence on the mental state of these people. The aim of this study was to investigate the effect of an antipsychotic treatment on the blood levels of MMP-3, as well as investigating its relationship with insight into schizophrenia. METHODS: Thirty people with schizophrenia were included in the study. The concentration of MMP-3 in the blood serum was assessed using enzyme-linked immunosorbent assay. Insight into the disease was assessed using the Beck Cognitive Insight Scale. RESULTS: The antipsychotic treatment applied decreased the levels of MMP-3 in patients with schizophrenia (p = 0.005), however, the statistically significant interaction (p = 0.02) indicates that the decrease only concerned men. There was also a statistically significant correlation between the level of MMP-3 and insight into the disease (p = 0.02). CONCLUSION: MMP-3 may be associated with gender, treatment and symptoms in schizophrenic patients.KEY POINTSMMP3 could be used as a potential biomarker for schizophrenia.The level of MMP-3 decreased due to the applied antipsychotic treatment.The higher the level of MMP-3 in a group of people with schizophrenia, the better insight into their disease.

Mechanisms Underlining Inflammatory Pain Sensitivity in Mice Selected for High and Low Stress-Induced Analgesia-The Role of Endocannabinoids and Microglia.

In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3-3 mg/kg) prior to formalin. Minocycline (45 and 100 mg/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg/kg, i.p.). Cannabinoid receptor types 1 and 2 (Cnr1, Cnr2) and opioid receptor subtype (Oprm1, Oprd1, Oprk1) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher Cnr1 transcription. Downregulation of Oprd1 and Oprm1 mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced Aif1 and Il-1ß mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus.

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.

Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification.

Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.

Cannabidiol (CBD) Protects Adipose-Derived Mesenchymal Stem Cells (ASCs) against Endoplasmic Reticulum Stress Development and Its Complications.

BACKGROUND: Recent studies suggested that individuals with metabolic disorders have altered function of adipocytes and adipose stem cell subpopulations, which impairs tissue homeostasis, promoting insulin resistance and diabetes development. The non-psychoactive phytocannabinoid CBD was found to modulate adipose tissue metabolism, however, its exact role in controlling ASCs' fate is still poorly understood. OBJECTIVES: This investigation aimed to elucidate whether pretreatment of ASCs with CBD can protect against ER stress development and maintain the cytophysiological properties of cells. METHODS: Human ASCs were cultured under control and adipogenic conditions. Prior to the experiments, cells in the experimental group were pretreated with CBD following the addition of an ER stress inducer-tunicamycin. After the experiments, the cells were subsequently tested for expression of the apoptotic, ER stress, and anti-inflammatory-related genes using RT-qPCR. Oxidative stress was analysed with flow cytometric assays. RESULTS: Cells pretreated with CBD displayed decreased apoptosis and enhanced proliferation rate. Additionally, the expression of pro-inflammatory cytokines and miRNAs was significantly reduced. The obtained results also demonstrated an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the down-regulation of IRE-1, PERK, CHOP, and ATF6 transcripts upon CBD treatment. CONCLUSION: The presented data provide the evidence that CBD protects ASCs against ER stress development and its complications and, thus, offers new insights for the management of obesity through the regulation of adipose tissue dynamics.

Polypharmacotherapy in Psychiatry: Global Insights from a Rapid Online Survey of Psychiatrists.

In recent years, an increase in the problem of polypharmacotherapy in psychiatric patients has been observed, including the widespread problem of groups of people taking new psychoactive substances. One reason for this problem may be the poor knowledge of pharmacological interactions in psychiatry. The aim of this study was to explore the opinions and knowledge of psychiatrists from around the world on various aspects related to polypharmacotherapy. A total of 1335 psychiatrists from six continents were included in the study. The respondents' opinion on the problem of hepatotoxicity in psychiatry was also examined. The greatest discrepancy among psychiatrists from different continents in the answers given concerned the definition of polypharmacotherapy (p < 0.001) and the approach to hepatotoxicity (p < 0.001). It is noteworthy that only about 20% of the psychiatrists surveyed (p < 0.001) believe that polypharmacotherapy is associated with a higher rate of patients' hospitalisations. The most commonly used type of polypharmacy by psychiatrists was antidepressants and antipsychotics. Most of them also stated that polypharmacy was associated with reduced patient compliance with the doctor's recommendations related to taking medications due to the increased complexity of the therapy. The continent that diversified the analysed questions to the greatest extent was Africa. Future educational activities for trainee psychiatrists should include more discussion of polypharmacotherapy in psychiatry.

Gold (III) Derivatives in Colon Cancer Treatment.

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

Manganese concentration in patients with encephalopathy following ephedrone use: a narrative review and analysis of case reports.

BACKGROUND: Numerous case reports describe manganese encephalopathy in patients using ephedrone (methcathinone). The aim of this narrative review of case reports was to relate manganese ion concentrations in peripheral blood to the reported neurological deficits. METHODS: International databases, including Thomson (Web of Knowledge), PubMed/Medline, Science Direct, Scopus and Google Scholar were searched for literature items published between 2007 and 2020, in which the authors measured the manganese concentration in patients taking ephedrone. RESULTS: We identified 39 patients in two case series comprising of twenty-three and twelve patients, respectively, and four case reports meeting inclusion criteria. The study showed that 93% of them had elevated blood manganese concentration in relation to the accepted norm (>219 nmol/L), and the median was 364 nmol/L. The median duration of ephedrone use in individual groups of patients was approximately 48 months, and it did not show a relationship with the manganese concentration in the blood. A greater percentage of the people with manganese concentration higher than 250 nmol/L exhibited more severe gait, speech and handwriting disorders. The median duration of ephedrone withdrawal was a month in the group of people with the highest level of manganese ions (>500 nmol/L). CONCLUSION: Manganese concentrations did not vary with the duration of ephedrone use.

Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain-A Biomedical Mechanism of Action.

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg2+), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg2+ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg2+ (40 mg/kg intraperitoneally). Mg2+ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg2+ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.

Psychoactive Substances Taken with Mephedrone and HCV Infection.

BACKGROUND: In recent years, the observed frequency of hospitalization of patients taking mephedrone with other psychoactive substances has increased. There are no data in the literature on the effect of mephedrone use on liver function in patients, including the frequency of HCV infection. We have analysed the impact of taking mephedrone together with other psychoactive substances on the incidence of HCV infection. We have also analysed the effect of taking mephedrone with heroin, alcohol, and benzodiazepines on liver enzyme levels. METHODS: The study included patients taking mephedrone with: alcohol (n = 115), heroin (n = 85) and benzodiazepines (n = 130) hospitalized in 2010-2018. The control group consisted of patients addicted to alcohol (n = 180), heroin (n = 221) and benzodiazepines (n = 152). Clinical data and laboratory findings were collected from medical records. RESULTS: Taking mephedrone together with benzodiazepines is a statistically significant predictor of HCV infection in this group of patients, OR (8.44); 95% CI 5.63-12.64; p < 0.001). A statistically significant interaction of the group with HCV infection was observed, i.e., for the level of alanine transaminase (p < 0.001) and aspartate transaminase (p < 0.001). Increased levels of liver enzymes in each of the studied groups was characteristic in patients with HCV infection (p < 0.001). Taking additional mephedrone by this group of patients did not increase the level of liver enzymes. CONCLUSION: HCV infection is a statistically significant factor affecting the increase in liver enzymes levels in the group of patients taking mephedrone.

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System.

The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood-brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

Nitric oxide modulates tapentadol antinociceptive tolerance and physical dependence.

Tapentadol, an analgesic with a dual mechanism of action, involving both µ-opioid receptor agonism and noradrenaline reuptake inhibition (MOP-NRI), was designed for the treatment of moderate to severe pain. However, the widely acknowledged risk of analgesic tolerance and development of physical dependence following sustained opioid use may hinder their effectiveness. One of the possible mechanisms behind these phenomena are alterations in nitric oxide synthase (NOS) system activity. The aim of the study was to investigate the tolerance and dependence potential of tapentadol in rodent models and to evaluate the possible role of nitric oxide (NO) in these processes. Our study showed that chronic tapentadol treatment resulted in tolerance to its antinociceptive effects to an extent similar to tramadol, but much less than morphine. A single injection of a non-selective NOS inhibitor, NG-nitro-L-arginine (L-NOArg), reversed the tapentadol tolerance. In dependence studies, repeated administration of L-NOArg attenuated naloxone-precipitated withdrawal in tapentadol-treated mice, whereas a single injection of L-NOArg was ineffective. Biochemical analysis revealed that tapentadol decreased nNOS protein levels in the dorsal root ganglia of rats following 31 days of treatment, while no significant changes were found in iNOS and eNOS protein expression. Moreover, pre-treatment with L-NOArg augmented tapentadol antinociception in an opioid- and α2-adrenoceptor-dependent manner. In conclusion, our data suggest that the NOS system plays an important role in the attenuation of tapentadol-induced tolerance and withdrawal. Thus, inhibition of NOS activity can serve as a promising treatment option for long-term tapentadol use by extending its effectiveness and improving the side-effects profile.