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Updated: Aug 10, 2025
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and
Lynnea D Harris1, Michael C Regan2,3, Scott J Myers4
1Department of Chemistry, Emory University, Atlanta, Georgia30322, United States.
Abstract:
Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing N-methyl-d-Aspartate receptors is thought to play a key role in mechanisms underlying cellular adaptation that takes place in the development of analgesic tolerance. Herein, we describe a novel GluN2B-selective negative allosteric modulator, EU93-108, that shows high potency and brain penetrance. We describe the structural basis for binding at atomic resolution. This compound possesses intrinsic analgesic properties in the rodent tail immersion test. EU93-108 has an acute and significant anodyne effect, whereby morphine when combined with EU93-108 produces a higher tail flick latency compared to that of morphine alone. These data suggest that engagement of GluN2B as a target has utility in the treatment of pain, and EU93-108 could serve as an appropriate tool compound to interrogate this hypothesis. Future structure-activity relationship work around this scaffold could give rise to compounds that can be co-administered with opioids to diminish the onset of tolerance due to chronic opioid use, thereby modifying their utility.
Insights
A novel compound, EU93-108, targets GluN2B receptors to reduce opioid tolerance. This may help manage pain and prevent overdose deaths linked to chronic opioid use.
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Chronic opioid use leads to tolerance, addiction, and overdose deaths.
- Overactivation of GluN2B-containing N-methyl-D-aspartate receptors is implicated in analgesic tolerance.
- Developing strategies to mitigate opioid tolerance is crucial for pain management and public health.
Purpose of the Study:
- To identify and characterize a novel GluN2B-selective negative allosteric modulator.
- To investigate the potential of targeting GluN2B for pain treatment and mitigating opioid tolerance.
Main Methods:
- Design and synthesis of EU93-108, a GluN2B-selective negative allosteric modulator.
- Structural analysis of EU93-108 binding at atomic resolution.
- Assessment of analgesic properties and synergistic effects with morphine in rodent models (tail immersion test).
Main Results:
- EU93-108 demonstrated high potency and brain penetrance.
- The compound possesses intrinsic analgesic effects and potentiates morphine's analgesic action.
- Structural data provided atomic resolution insights into the binding mechanism.
Conclusions:
- Targeting GluN2B receptors offers a promising therapeutic strategy for pain management.
- EU93-108 serves as a valuable tool compound for further research into GluN2B's role in pain and tolerance.
- Future drug development could lead to co-administered therapies to reduce opioid tolerance and improve patient outcomes.
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