In vitro functional assays as a tool to study new synthetic opioids at the µ-opioid receptor: Potential, pitfalls and progress.

New psychoactive substances (NPS), formerly also referred to as "designer drugs", are often synthetic derivatives of existing psychoactive drugs, their diverse structures aiming at circumventing legislation and detection while their effects mimic those of traditional drugs of abuse. Of these, the group of new synthetic opioids (NSOs) has been one of the fastest growing NPS subclasses in the last couple of years, with over 70 new compounds detected in Europe since 2009. Apart from effects such as euphoria and analgesia, opioid use is associated with severe side effects such as constipation and respiratory depression. The µ-opioid receptor (MOR), a class A G protein-coupled receptor, is responsible for most of the therapeutic and adverse opioid effects. Insight into the pharmacology of opioids can aid the implementation of proactive harm reduction strategies, as well as the development of safer opioid analgesics. This review aims at assembling the available information on in vitro MOR agonism of the emerging class of new synthetic opioids, with a special focus on functional assays monitoring G protein and ß-arrestin pathways.