NSO_MAP - Shedding new lights on the emerging New Synthetic Opioids of "Nitazene" class: a Multidisciplinary Pharmaco-toxicological and Analytical approach towards forensic investigation

Abstract:

Due to the lack of knowledge on the chemical and the pharmaco-toxicological properties of the highly potent New Synthetic Opioids (NSO) belonging to the group of 2-benzylbenzimidazoles, known also as “Nitazenes”, our project is aimed to fill the gaps in this field. In particular, our project will be focused on a complete characterization and categorization of these new compounds, by evaluating, in vivo, the pharmaco-toxicological effects (UniFE) and, in vitro, cytotoxicity and genotoxicity of detected Nitazene opioids or their metabolites. The multidisciplinary approach used will provide new methods and information to support forensic investigations. Metabolism of selected Nitazenes will be studied through in vitro/in vivo approaches and LC-HRMS analysis. Nitazenes metabolites characterization is crucial for their univocal identification in case of acute intoxication, as well as, for unambiguous detection and determination in biological fluids. In vivo safety pharmacology tests will be performed to identify the pharmaco-toxicological effects of the single or repeated administration of Nitazenes and of their main metabolites on sensorimotor, neurological, cardio-vascular and respiratory changes, in both male and female mice to assess the role of gender in Nitazenes toxicity. These tests are crucial to compare the level of potencies between these molecules, the role of the chemical modification on the alteration of vital parameters (respiration/heart rate) and the correlation of these effects to those reported in emergency units with the same drugs. To obtain a rapid behavioural screening of Nitazenes tested and to reduce the number of rodents, the zebrafish larvae model will be also used. Finally, an innovative flow cytometry protocol will allow a rapid, effective in vitro cyto- geno-toxicity evaluation of Nitazenes and their metabolites. The potential involvement of oxidative stress and inflammation will be also considered, in order to identify the possible mechanisms underlying the observed effects. In the short term, the new data may be beneficial to governmental and non-governmental organizations, helping integrated strategies for prevention, screening, and linkage to drug abuse treatment programs. In the long-term the community will benefit from improved control over the global NSO crises.