Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans
Author(s)
Type
Journal Article
Abstract
Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the mu-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-beta-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.
Date Issued
2011
Citation
Mol Psychiatry, 2011, 16, pp.826-785
ISSN
1476-5578
Publisher
NATURE PUBLISHING GROUP
Start Page
826
End Page
785
Journal / Book Title
Mol Psychiatry
Volume
16
Issue
8
Copyright Statement
© 2011 Macmillan Publishers Limited All rights reserved. This work is licensed under the Creative
Commons Attribution-NonCommercial-
No Derivative Works 3.0 Unported License. To view
a copy of this license, visit http://creativecommons.
org/licenses/by-nc-nd/3.0/
Commons Attribution-NonCommercial-
No Derivative Works 3.0 Unported License. To view
a copy of this license, visit http://creativecommons.
org/licenses/by-nc-nd/3.0/
Description
17/12/14 meb. OA paper, Ok to add.
Identifier
http://www.ncbi.nlm.nih.gov/pubmed/21502953
Subjects
Adult Amygdala/*drug effects/physiology/radionuclide imaging Brain/drug effects/*physiology/radionuclide imaging Brain Mapping/methods Corpus Striatum/*drug effects/physiology/radionuclide imaging Dose-Response Relationship, Drug Fentanyl/analogs & derivatives/diagnostic use Food Humans Indans/blood/pharmacokinetics/*pharmacology Male Middle Aged Naltrexone/blood/pharmacokinetics/pharmacology Narcotic Antagonists/*pharmacology Radioligand Assay/methods *Reward Triazoles/blood/pharmacokinetics/*pharmacology
Publication Status
Published