Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Opioid analgesics remain a gold standard for the treatment of moderate to severe pain. However, their clinical utility is seriously limited by a range of adverse effects. Among them, their high-addictive potential appears as very important, especially in the context of the opioid epidemic. Therefore, the development of safer opioid analgesics with low abuse potential appears as a challenging problem for opioid research. Among the last few decades, different approaches to the discovery of novel opioid drugs have been assessed. One of the most promising is the development of G protein-biased opioid agonists, which can activate only selected intracellular signaling pathways. To date, discoveries of several biased agonists acting via μ-opioid receptor were reported. According to the experimental data, such ligands may be devoid of at least some of the opioid side effects, such as respiratory depression or constipation. Nevertheless, most data regarding the addictive properties of biased μ-opioid receptor agonists are inconsistent. A global problem connected with opioid abuse also requires the search for effective pharmacotherapy for opioid addiction, which is another potential application of biased compounds. This review discusses the state-of-the-art on addictive properties of G protein-biased μ-opioid receptor agonists as well as we analyze whether these compounds can diminish any symptoms of opioid addiction. Finally, we provide a critical view on recent data connected with biased signaling and its implications to in vivo manifestations of addiction. GRAPHIC ABSTRACT: [Image: see text]