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Updated: Jul 16, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity

Daozhong Jin, Hong Chen, Yuying Huang

    The Journal of Clinical Investigation
    |July 14, 2026
    PubMed

    Insights

    Opioid-induced pain hypersensitivity and tolerance involve NMDA receptor (NMDAR) hyperactivity. BRAF kinase translocation to spinal cord synaptosomes drives this NMDAR overactivity, impacting pain management.

    Area of Science:

    • Neuroscience
    • Pharmacology
    • Molecular Biology

    Background:

    • Opioids are vital for severe pain but cause hyperalgesia and tolerance.
    • NMDA receptor (NMDAR) hyperactivity in the spinal cord contributes to these opioid-induced effects.
    • The precise signaling pathways driving NMDAR hyperactivity remain poorly understood.

    Purpose of the Study:

    • To elucidate the molecular mechanisms linking opioid administration to NMDAR hyperactivity.
    • To investigate the role of BRAF kinase in mediating opioid-induced hyperalgesia and tolerance.
    • To explore the therapeutic potential of targeting BRAF for improved opioid analgesia.

    Main Methods:

    • Morphine administration in rats to induce hyperalgesia and tolerance.
    • Assessment of BRAF translocation, MEK-ERK phosphorylation, and NMDAR activity in spinal cord synaptosomes.
    • Pharmacological inhibition of BRAF (vemurafenib) and MEK.
    • Conditional knockout of Braf in dorsal root ganglion (DRG) neurons.
    • Electrophysiological recordings of NMDAR hyperactivity in spinal dorsal horn neurons.
    • Evaluation of analgesic effects, hyperalgesia, and tolerance in response to BRAF inhibition or Braf deletion.

    Main Results:

    • Morphine promoted BRAF translocation to spinal cord synaptosomes, increasing MEK-ERK phosphorylation.
    • BRAF physically interacted with NMDARs in both rat and human spinal cords.
    • BRAF inhibition (vemurafenib) or Braf deletion reversed morphine-induced NMDAR phosphorylation, trafficking, and hyperactivity.
    • Targeting BRAF or MEK, or deleting Braf, enhanced morphine analgesia and reduced hyperalgesia and tolerance.

    Conclusions:

    • BRAF overactivity at nociceptor central terminals is a key mediator of opioid-induced NMDAR hyperactivity.
    • BRAF kinase signaling is critical for the development of opioid-induced hyperalgesia and tolerance.
    • Clinically approved BRAF inhibitors may offer a strategy to enhance opioid efficacy and mitigate adverse effects.
    Keywords:
    Drug therapyNeurological disordersNeuroscienceOncology

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