Summary: Researchers at Scripps Research have identified a promising new approach to treating opioid use disorder (OUD) by using a compound that targets metabotropic glutamate 2 (mGlu2) receptors. The investigational drug, ADX106772, reduced oxycodone self-administration and cue-induced drug-seeking in an animal model without impairing natural reward behaviors, pointing to a potential new therapy for prescription opioid addiction.
The compound ADX106772 is a positive allosteric modulator of the mGlu2 receptor developed by Addex. In preclinical tests on rats dependent on oxycodone, ADX106772 lowered opioid intake for extended periods and decreased relapse-like behavior when animals were re-exposed to drug-associated cues. Importantly, the treatment did not reduce motivation for a highly palatable, non-drug reward (sweetened condensed milk), indicating selective effects on drug-seeking circuits rather than a broad suppression of reward.
Key Facts:
- ADX106772, developed by Addex, selectively reduced oxycodone intake and cue-induced seeking in a rat model of opioid use disorder without disrupting other reward-driven behaviors.
- More than two million people in the U.S. are estimated to live with OUD, and opioid overdoses claim tens of thousands of lives each year; semi-synthetic opioids such as oxycodone account for a substantial share of prescription opioid-related deaths.
- This study supports the therapeutic potential of targeting the glutamate system—specifically mGlu2 receptors—as a strategy to reduce opioid consumption and prevent relapse in prescription opioid use disorder.
Source: Scripps Research Institute
Background
Over the past decade, opioid misuse and overdose have become a major public health crisis in the United States. Although medications such as methadone, buprenorphine and naltrexone help many patients, relapse rates remain high and better treatment options are needed. Accumulating research implicates glutamate signaling in the neural processes that drive craving and relapse, making glutamatergic targets attractive for new pharmacotherapies.
Study overview and methods
Investigators trained male Wistar rats to self-administer oxycodone intravenously (0.15 mg/kg per infusion) for long daily sessions, pairing drug delivery with a distinct light-and-noise cue. These drug-associated cues serve as conditioned stimuli that reliably trigger craving-related circuits and reinstate drug-seeking after abstinence. A parallel group of animals was trained to obtain a tasty nondrug reinforcer—diluted sweetened condensed milk—so the researchers could assess whether drug effects were specific to opioid seeking rather than general motivation for rewards.
After dependence was established, the team administered ADX106772 subcutaneously at several doses and measured oxycodone self-administration, as well as the conditioned reinstatement of drug-seeking following extinction when the cue was reintroduced without drug availability. The same protocol was used to test for effects on sweetened condensed milk taking and seeking.
Results
ADX106772 significantly reduced oxycodone self-administration for up to 12 hours after a single administration. Higher doses produced a faster onset of action. In relapse-model tests, animals that received ADX106772 were far less likely to resume lever-pressing when exposed to the drug-associated cue, indicating a reduction in conditioned reinstatement of drug-seeking. Crucially, the compound did not alter the animals’ intake of, or motivation for, the palatable nondrug reinforcer, demonstrating behavioral selectivity.
Interpretation and implications
These findings suggest that enhancing mGlu2 receptor activity can reduce oxycodone consumption and blunt cue-triggered relapse in preclinical models of OUD. Because mGlu2 activation inhibits glutamate release in brain regions tied to reward and addiction, ADX106772 likely dampens the glutamatergic drive that contributes to craving and relapse. Previous work with similar mechanisms has shown efficacy against motivated behaviors for cocaine, nicotine and alcohol, and this study extends that evidence to prescription opioids.
Selective suppression of drug-directed behavior without impairing normal reward seeking is an important therapeutic characteristic, as nonselective suppression could produce adverse effects such as loss of appetite or anhedonia. The authors note, however, that opioid use disorder involves persistent vulnerability to craving after extended abstinence, so chronic or repeated dosing will need careful evaluation to determine long-term efficacy and safety, including any off-target behavioral effects.
Quotes from the research team
“Our research demonstrates that targeting the glutamate system with novel pharmacotherapies can stop oxycodone self-administration and seeking in preclinical models, which supports this approach as a future potential treatment for prescription opioid use disorder,” said Rémi Martin-Fardon, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.
“By reducing the release of glutamate, our study was designed to thereby reduce the effects of the drug and withdrawal on the brain,” said Jessica Illenberger, PhD, first author and postdoctoral research associate in the Martin-Fardon laboratory.
Authorship and funding
Authors listed for the study “ADX106772, an mGlu2 receptor positive allosteric modulator, selectively attenuates oxycodone taking and seeking” include Rémi Martin-Fardon and Jessica Illenberger, with contributions from Francisco J. Flores-Ramirez, Alessandra Matzeu of Scripps Research, and Robert Lütjens of Addex Pharmeceuticals.
Funding: This work was supported by grants from the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse (AA026999, AA028549, AA006420, T32AA007456, DA053443).
About this neuropharmacology and OUD research news
Author: Scripps Communications
Source: Scripps Research Institute
Contact: Scripps Communications – Scripps Research Institute
Image credit: Neuroscience News
Original research: Open access. The study was published in the journal Neuropharmacology on July 20, 2023, reporting preclinical evidence that mGlu2 receptor positive allosteric modulation can selectively reduce oxycodone taking and seeking without affecting motivation for a palatable nondrug reinforcer.
Abstract
ADX106772, an mGlu2 receptor positive allosteric modulator, selectively attenuates oxycodone taking and seeking.
Opioid abuse and overdose are major public health problems, with oxycodone being a commonly misused prescription opioid. Treatments that reduce relapse vulnerability by limiting the reinforcing effects of drug or alleviating withdrawal-driven craving are critically needed. The glutamate system plays a key role in drug-seeking behaviors. Agonists and positive allosteric modulators of mGlu2 reduce glutamate activity and have been shown to decrease the intake and seeking of several drugs of abuse.
In this study, male Wistar rats were trained to self-administer oxycodone or a palatable nondrug reward in the presence of a contextual/discriminative stimulus. ADX106772 dose-dependently decreased oxycodone self-administration and prevented cue-induced reinstatement of oxycodone seeking, while leaving non-drug reward taking and cue-induced seeking for that reward unaffected. These results support mGlu2 positive allosteric modulation as a potential therapeutic strategy for prescription opioid use disorder.