Background and aims: Opioids are highly effective analgesics yet produce several undesired effects. Numerous study showed that opioid analgesia is mediated by the G protein signaling, whereas some side effects are connected with the functions of the regulatory protein, β-arrestin-2. Therefore, synthesis of novel ligands biased toward G protein pathway with minimal recruitment of β-arrestin-2 appears as a promising way of development of novel, effective and safer opioid therapeutics. Here, we aimed to investigate antinociceptive profile of a novel G protein-biased μ opioid receptor agonist, PZM21 and its influence on addiction-like behavioral effects in rodents.
Methods: PZM21-induced antinociception was assessed using tail flick test and was measured after systemic and intrathecal drug administration in C57BL6/J mice and Wistar rats, respectively. To study for potential addictive properties of PZM21, mice were tested for PZM21-induced tolerance, conditioned place preference, locomotor sensitization and withdrawal. Furthermore, we investigated the effects of PZM21 in self-administration paradigm in Sprague-Dawley rats.
Results: We demonstrate that treatment with PZM21 results in long-lasting dose-dependent and μ opioid receptor-mediated antinociception after both systemic and intrathecal administration. PZM21 does not induce reinforcing effects in conditioned place preference, locomotor sensitization and self-administration paradigms. However, repeated administration of this compound causes rapid development of antinociceptive tolerance and leads to the occurrence of withdrawal symptoms. 
Conclusions: Our results indicate that PZM21 presents antinociceptive efficacy, but at the same time induces physical dependence. However, its nonrewarding profile suggests that G protein-biased ligands may be considered as a promising class of novel opioid therapeutics.

ANTINOCICEPTIVE PROFILE OF A NOVEL G PROTEIN-BIASED OPIOID, PZM21 AND ITS EFFECTS ON ADDICTION-LIKE BEHAVIOR IN RODENTS