Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using S-GTPγS binding assays. While all of the agonists act as p...

Full description

Saved in:
Bibliographic Details
Published in:Biomolecules (Basel, Switzerland) Switzerland), 2023-06, Vol.13 (6), p.935
Main Authors: Acevedo-Canabal, Agnes, Grim, Travis W, Schmid, Cullen L, McFague, Nina, Stahl, Edward L, Kennedy, Nicole M, Bannister, Thomas D, Bohn, Laura M
Format: Article
Language:English
Subjects:
Agonists
Agonists (Biochemistry)
Analgesics
Analgesics, Opioid - pharmacology
Animals
biased agonism
Dosage and administration
Drug efficacy
Females
Fentanyl
Fentanyl - pharmacology
GPCR
Hyperactivity
Laboratory animals
Locomotor activity
Membrane proteins
Mice
Morphine
Morphine - pharmacology
Narcotics
Neostriatum
oliceridine
Opioid receptors (type mu)
Opioids
Pain perception
partial agonist
Pharmacology, Experimental
Physiological aspects
Proteins
Software
Spiro Compounds
SR-17018
striatum
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom13060935