Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.
Analgesics, Opioid
/ administration & dosage
Animals
Behavior, Animal
/ drug effects
Dose-Response Relationship, Drug
Drug Delivery Systems
Injections, Intravenous
Injections, Spinal
Locomotion
/ drug effects
Male
Mice
Mice, Inbred C57BL
Morphine
/ antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Rats, Wistar
Structure-Activity Relationship
Thiophenes
/ administration & dosage
Urea
/ administration & dosage
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
25
03
2019
revised:
15
07
2019
accepted:
16
07
2019
pubmed:
28
7
2019
medline:
23
9
2020
entrez:
27
7
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31347704
doi: 10.1111/bph.14805
pmc: PMC6932942
doi:
Substances chimiques
Analgesics, Opioid
0
PZM21 compound
0
Thiophenes
0
Morphine
76I7G6D29C
Urea
8W8T17847W
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4434-4445Informations de copyright
© 2019 The British Pharmacological Society.
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