mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors

The Journal of Neuroscience, 2023 · DOI: https://doi.org/10.1523/JNEUROSCI.0601-23.2023 · Published: August 2, 2023

Simple Explanation

Opioids, while effective for severe pain, can paradoxically induce pain hypersensitivity and tolerance, requiring increased doses and posing overdose risks. This study investigates how opioids cause this pain hypersensitivity. The research demonstrates that opioids trigger the movement of mGluR5, a glutamate receptor, from peripheral sensory neurons to the spinal cord. In the spinal cord, mGluR5 interacts with NMDARs, another type of glutamate receptor, enhancing their synaptic expression and activity. This interaction amplifies pain signals from sensory neurons to the spinal cord. Inhibiting mGluR5 or disrupting its interaction with NMDARs could potentially reduce opioid-induced pain hypersensitivity and improve opioid effectiveness.

Study Duration

7-8 days morphine/fentanyl treatment

Participants

Adult male and female Sprague Dawley rats (180-250g) and C57BL/6 mice (8-12 weeks old)

Evidence Level

Level II: Experimental study using animal models

Key Findings

1
Repeated opioid treatment reduces mGluR5 protein levels in the DRG but increases them in the spinal cord, suggesting trafficking from DRG to spinal cord.
2
mGluR5 in the spinal cord interacts directly with GluN1, an NMDAR subunit, and this interaction is increased by repeated morphine treatment.
3
Conditional mGluR5 knockdown in DRG neurons attenuates morphine-induced hyperalgesia and tolerance, indicating that mGluR5 from primary sensory neurons mediates these effects.

Research Summary

The study investigates the role of mGluR5, a glutamate receptor, in opioid-induced hyperalgesia and tolerance. It reveals that repeated opioid treatment promotes mGluR5 trafficking from DRG neurons to the spinal cord. In the spinal cord, mGluR5 forms homodimers and interacts with NMDARs, augmenting their synaptic expression and activity. This interaction contributes to increased glutamatergic input to the spinal dorsal horn. Conditional mGluR5 knockdown in DRG neurons attenuates morphine-induced hyperalgesia and tolerance, suggesting that mGluR5 from primary sensory neurons mediates these opioid-induced adverse effects.

Practical Implications

Therapeutic Target Identification

Inhibiting mGluR5 activity or disrupting the mGluR5–NMDAR interaction may offer new therapeutic strategies for treating opioid-induced hyperalgesia and tolerance.

Improving Opioid Efficacy

Targeting mGluR5 could potentially improve the efficacy of opioids for pain control by reducing the development of tolerance and hyperalgesia.

Understanding Pain Mechanisms

The findings contribute to a better understanding of the complex signaling mechanisms underlying opioid-induced pain hypersensitivity and tolerance.

Study Limitations

1
The study is performed on animal models, and the results may not be directly translatable to humans.
2
The exact mechanisms by which opioid treatment potentiates mGluR5 trafficking from DRG neurons to the spinal cord remain unclear.
3
Further research is needed to validate the role of mGluR5 phosphorylation and interaction with motor proteins in opioid-induced hyperalgesia.

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