Functional characterization of a novel opioid, PZM21, and its influence on behavioural responses to morphine

The concept of opioid ligands biased toward the G protein pathway with minimal recruitment of β-arrestin-2 has become a promising approach for the development of novel, efficient and potentially nonaddictive opioid therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21, was reported to be analgesic and possess reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21.We evaluated antinociceptive effects of systemic and intrathecal PZM21 administration. Its addiction-like properties were determined using several behavioural approaches: conditioned place preference, locomotor sensitization, precipitated withdrawal and self-administration. Further, we assessed the influence of PZM21 on morphine-induced antinociception, tolerance and reward. Effects of PZM21 on striatal release of monoamines were evaluated using brain microdialysis.PZM21 caused long-lasting dose-dependent antinociception. It did not induce reward- and reinforcement-related behaviour, however, its repeated administration led to antinociceptive tolerance and naloxone-precipitated withdrawal symptoms. Pretreatment with PZM21 enhanced morphine-induced antinociception and attenuated the expression of morphine reward. In comparison to morphine, PZM21 administration led to moderate release of dopamine and robust release of serotonin in the striatum.PZM21 presents antinociceptive efficacy and does not possess rewarding or reinforcing properties. However, its clinical application may be restricted, as it induces tolerance and withdrawal symptoms. Notably, its ability to diminish morphine reward implicates that PZM21 may be useful in opioid use disorder therapy