Three fentanyl analogues Acrylfentanyl, Ocfentanyl and Furanylfentanyl are potent, rapid-acting synthetic analgesics that recently appeared on the illicit market of new psychoactive substances (NPS) ...under the class of new synthetic opioids (NSO). Pharmacotoxicological data on these three non-pharmaceutical fentanyl analogues are limited and studies on their genotoxicity are not yet available. Therefore, the aim of the present study was to investigate this property. The ability to induce structural and numerical chromosomal aberrations in human lymphoblastoid TK6 cells was evaluated by employing the flow cytometric protocol of the in vitro mammalian cell micronucleus test. Our study demonstrated the non-genotoxicity of Fentanyl, i.e., the pharmaceutical progenitor of the class, while its illicit non-pharmaceutical analogues were found to be genotoxic. In particular, Acrylfentanyl led to a statistically significant increase in the MNi frequency at the highest concentration tested (75 μM), while Ocfentanyl and Furanylfentnyl each did so at both concentrations tested (150, 200 μM and 25, 50 μM, respectively). The study ended by investigating reactive oxygen species (ROS) induction as a possible mechanism linked to the proved genotoxic effect. The results showed a non-statistically significant increase in ROS levels in the cultures treated with all molecules under study. Overall, the proved genotoxicity raises concern about the possibility of serious long-term consequences.
Novel Psychoactive Substances (NPS) include several classes of substances such as synthetic cannabinoids (SCBs), an emerging alternative to marijuana, easily purchasable on internet. SCBs are more ...dangerous than Δ
-Tetrahydrocannabinol as a consequence of their stronger affinities for the CB
and CB
receptors, which may result in longer duration of distinct effects, greater potency, and toxicity. The information on SCBs cytotoxicity, genotoxicity, mutagenicity, and long-term effects is scarce. This fact suggests the urgent need to increase available data and to investigate if some SCBs have an impact on the stability of genetic material. Therefore, the aim of the present study was the evaluation of the mutagenic effect of different SCBs belonging to indole- and indazole-structures. The analyzes were conducted in vitro on human TK6 cells and mutagenicity were measured as micronucleus fold increase by flow cytometry. Our results have highlighted, for the first time, the mutagenic capacity of four SCBs, in particular in terms of chromosomal damage induction. We underline the serious potential toxicity of SCBs that suggests the need to proceed with the studies of other different synthetic compounds. Moreover, we identified a method that allows a rapid but effective screening of NPS placed on the market increasingly faster.
Recreational use of illicit methiopropamine (MPA) is a public health concern because it produces neurochemical effects comparable with those induced by methamphetamine (METH). The present study ...investigated the effects of MPA on the expression of an aggressive behaviour. Eighty CD-1 male mice, after receiving intraperitoneal injection of saline, MPA (0.01–10 mg/kg), METH (0.01–10 mg/kg), or AMPH (0.01–10 mg/kg), once a week over a 5-week period, underwent the resident–intruder test and spontaneous locomotor activity measurement. Results showed that all psychostimulants induce aggressive behaviour even at low doses, with a dose-dependent increase and a time-dependent sensitisation. MPA potency was similar to METH and superior to AMPH. Therefore, MPA-induced aggressive behaviour may appear even at MPA dosages free of cardiovascular or other behavioural adverse effects and could become a non-intentional side effect that users experience after increasing and repeating MPA consumption.
JWH-018 is the most known compound among synthetic cannabinoids (SCs) used for their psychoactive effects. SCs-based products are responsible for several intoxications in humans. Cardiac toxicity is ...among the main side effects observed in emergency departments: SCs intake induces harmful effects such as hypertension, tachycardia, chest pain, arrhythmias, myocardial infarction, breathing impairment, and dyspnea. This study aims to investigate how cardio-respiratory and vascular JWH-018 (6 mg/kg) responses can be modulated by antidotes already in clinical use. The tested antidotes are amiodarone (5 mg/kg), atropine (5 mg/kg), nifedipine (1 mg/kg), and propranolol (2 mg/kg). The detection of heart rate, breath rate, arterial oxygen saturation (SpO2), and pulse distention are provided by a non-invasive apparatus (Mouse Ox Plus) in awake and freely moving CD-1 male mice. Tachyarrhythmia events are also evaluated. Results show that while all tested antidotes reduce tachycardia and tachyarrhythmic events and improve breathing functions, only atropine completely reverts the heart rate and pulse distension. These data may suggest that cardiorespiratory mechanisms of JWH-018-induced tachyarrhythmia involve sympathetic, cholinergic, and ion channel modulation. Current findings also provide valuable impetus to identify potential antidotal intervention to support physicians in the treatment of intoxicated patients in emergency clinical settings.
N-methyl-2-pyrrolidone (NMP) and γ-hydroxybutyrate acid (GHB) are synthetic solvents detected in the recreational drug market. GHB has sedative/hypnotic properties and is used for criminal purposes ...to compromise reaction ability and commit drug-facilitated sexual assaults and other crimes. NMP is a strong solubilizing solvent that has been used alone or mixed with GHB in case of abuse and robberies. The aim of this experimental study is to compare the acute pharmaco-toxicological effects of NMP and GHB on neurological signs (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, and motor activity (bar, drag, and accelerod test) in CD-1 male mice. Moreover, since cardiorespiratory depression is one of the main adverse effects related to GHB intake, we investigated the effect of NMP and GHB on cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in mice. The present study demonstrates that NMP inhibited sensorimotor and motor responses and induced cardiorespiratory depression, with a lower potency and efficacy compared to GHB. These results suggest that NMP can hardly be used alone as a substance to perpetrate sexual assault or robberies.
Novel psychoactive substances (NPS) represent a broad class of drugs new to the illicit market that often allow passing drug-screening tests. They are characterized by a variety of structures, rapid ...transience on the drug scene and mostly unknown metabolic profiles, thus creating an ever-changing scenario with evolving analytical targets. The present study aims at developing an indirect screening strategy for NPS monitoring, and specifically for new synthetic opioids (NSOs), based on assessing changes in endogenous urinary metabolite levels as a consequence of the systemic response following their intake. The experimental design involved in-vivo mice models: 16 animals of both sex received a single administration of morphine or fentanyl. Urine was collected before and after administration at different time points; the samples were then analysed with an untargeted metabolomics LC-HRMS workflow. According to our results, the intake of opioids resulted in an elevated energy demand, that was more pronounced on male animals, as evidenced by the increase in medium and long chain acylcarnitines levels. It was also shown that opioid administration disrupted the pathways related to catecholamines biosynthesis. The observed alterations were common to both morphine and fentanyl: this evidence indicate that they are not related to the chemical structure of the drug, but rather on the drug class. The proposed strategy may reinforce existing NPS screening approaches, by identifying indirect markers of drug assumption.
Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, ...information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.
Abstract Objective To identify microRNAs (miRNAs) differentially expressed at early stages of gestation (12–14 weeks) in the serum of pregnant women, who later developed severe preeclampsia (sPE) in ...the third trimester of pregnancy ( n = 24) compared to women with normal pregnancy ( n = 24). Materials and Methods Sera from 12–14-week-gestation whole blood were subjected to microarray analysis with TaqMan Low Density Array chips (human microRNA panel V3.0), and to quantitative real-time polymerase chain reaction. Results By using the TaqMan Low Density Array chip technology, 19 mature miRNAs appeared differentially expressed in the group of women who later developed sPE as compared to normal women. The expression of four miRNAs (miR-1233, miR-520, miR-210, miR-144) was validated by quantitative real-time polymerase chain reaction analysis. MiR-1233 was the most overexpressed in the serum of women who later developed sPE. Conclusion Circulating miRNAs deserve further investigation in order to explore their potential role in the pathogenesis of preeclampsia. In particular, miR-1233 might represent a potential marker of early sPE.
MDPV is a synthetic cathinone illegally marketed and consumed for its psychostimulant effects, which are similar to those produced by cocaine, amphetamines, and MDMA. Clinical reports indicate that ...MDPV produces euphoria, increases alertness, and at high doses causes agitation, psychosis, tachycardia and hypertension, hallucinations, delirium, hyperthermia, rhabdomyolysis, and even death. In rodents, MDPV reproduces the typical physiological effects of psychostimulant drugs, demonstrating greater potency than cocaine. Nevertheless, its role in aggressive behavior has been reported but not yet experimentally confirmed. Therefore, the aim of this study was to evaluate the effects of acute and repeated MDPV (0.01–10 mg/kg i.p.) administration on aggressive behavior in mice and to compare them with those of cocaine (0.01–10 mg/kg i.p.) administration. To this purpose, the resident–intruder test in isolated mice and the spontaneous and stimulated aggressiveness tests for group-housed mice were employed. The present study shows for the first time that MDPV enhances aggressive behavior and locomotion in mice with greater potency and efficacy than cocaine treatment. Moreover, the aggressive and locomotor responses are enhanced after repeated administration, indicating that a sensitization mechanism comes into play. These results, although from preclinical investigation, are suggestive that human MDPV intake could be a problem for public health and the criminal justice system. Thus, investigation by police officers and medical staff is needed to prevent interpersonal violence induced by the consumption of synthetic cathinones.
Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine–dopamine reuptake inhibitor and, secondarily, as ...a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10–30 mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.
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