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

Abstract

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.

Keywords: Addiction; Dependence; G protein-biased opioids; Reward; Tolerance; Μ-opioid receptor.

Fig. 1

Chemical structures of discussed ligands. The figure presents chemical structures of agonists in the order they are discussed in the article: TRV130 (Oliceridine), kratom alkaloids, kurkinorin, carfentanil-amide opioids (MP102 as an exemplary member of this family of compounds), PZM21 and piperidine benzimidazoles (SR-compounds; SR-14968 and SR-17018 were chosen and discussed as the most interesting and promising compounds from this group)

Fig. 2

Activation of the μ-OR by unbiased and biased agonists. Following an unbiased agonist binding to the μ-OR both G_i/o protein- and β-arr2-dependent signaling pathways are activated. The conformation changes detach the G_i/oα and G_i/oβγ subunits of the heterotrimeric G protein. The G_i/oα subunit inhibits the activity of adenylate cyclase, reduces cAMP production, and leads to the activation of downstream signaling pathways, while the G_i/oβγ subunit inhibits voltage-gated calcium channels (VGCC) and activates G protein coupled inwardly rectifying potassium channels (GIRK) which results in hyperpolarization and inhibition of neuronal activity. This pathway is thought to mediate analgesia. On the other hand, the β-arr2-dependent pathway has been linked with undesirable opioid effects. It is hypothesized that the exclusion of this pathway using agonists with G protein bias may diminish opioid side effects, while preserving therapeutic ones