Functional characterization of a novel opioid, PZM21, and its influence on behavioural responses to morphine.
Br J Pharmacol. 2019-12-01; 176(23): 4434-4445
DOI: 10.1111/bph.14805
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BACKGROUND AND PURPOSE: The concept of opioid ligands biased towards the G
protein pathway with minimal recruitment of β-arrestin-2 is a promising approach
for the development of novel, efficient, and potentially nonaddictive opioid
therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21,
showed analgesic effects with reduced side effects. Here, we aimed to further
investigate the behavioural and biochemical properties of PZM21.
EXPERIMENT APPROACH: 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. Also, effects of
PZM21 on morphine-induced antinociception, tolerance, and reward were assessed.
Effects of PZM21 on striatal release of monoamines were evaluated using brain
microdialysis.
KEY RESULTS: 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 induced a moderate release of dopamine and a
robust release of 5-HT in the striatum.
CONCLUSIONS AND IMPLICATIONS: PZM21 exhibited antinociceptive efficacy, without
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 implies that PZM21 may be useful in treatment of
opioid use disorders.
© 2019 The British Pharmacological Society.
DOI: 10.1111/bph.14805
PMCID: PMC6932942 [Available on 2020-12-01]
PMID: 31347704