Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.
Br J Pharmacol
; 176(23): 4434-4445, 2019 12.
Article
in En
| MEDLINE
| ID: mdl-31347704
ABSTRACT
BACKGROUND AND PURPOSE:
The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of ß-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. EXPERIMENTAPPROACH:
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. KEYRESULTS:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiophenes
/
Urea
/
Behavior, Animal
/
Analgesics, Opioid
/
Locomotion
/
Morphine
Limits:
Animals
Language:
En
Journal:
Br J Pharmacol
Year:
2019
Type:
Article
Affiliation country:
Poland