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ResearchIn-Press PreviewNeuroscienceOncology Open Access | 10.1172/JCI201808

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

Daozhong Jin,1 Hong Chen,1 Yuying Huang,1 Shao-Rui Chen,1 and Hui-Lin Pan1

1Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Huoston, United States of America

Find articles by Jin, D. in: PubMed | Google Scholar

1Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Huoston, United States of America

Find articles by Chen, H. in: PubMed | Google Scholar

1Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Huoston, United States of America

Find articles by Huang, Y. in: PubMed | Google Scholar

1Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Huoston, United States of America

Find articles by Chen, S. in: PubMed | Google Scholar

1Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Center for Neuroscience and Pain Research, Department of Anesthesiology and, The University of Texas MD Anderson Cancer Center, Huoston, United States of America

Find articles by Pan, H. in: PubMed | Google Scholar

Published July 14, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201808.
Copyright © 2026, Jin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 14, 2026 - Version history
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Abstract

Opioids are essential analgesics for managing severe pain but can paradoxically increase pain sensitivity (hyperalgesia) and diminish analgesic efficacy (tolerance). Hyperactivity of NMDA-type glutamate receptors (NMDARs) at primary afferent terminals in the spinal cord contributes to both phenomena; however, the underlying signaling mechanisms remain unclear. Here, we report that morphine administration in rats promoted the translocation of monomeric BRAF, an oncogenic kinase, from the dorsal root ganglion (DRG) to spinal cord synaptosomes, leading to increased MEK-ERK phosphorylation at nociceptor central terminals. BRAF physically interacted with NMDARs in both rat and human spinal cords. Inhibition of BRAF activity with vemurafenib reversed morphine-induced NMDAR phosphorylation and synaptic localization of α2δ-1–bound NMDARs. Vemurafenib also abolished morphine-induced presynaptic NMDAR hyperactivity in spinal dorsal horn neurons. Correspondingly, conditional Braf knockout in DRG neurons normalized morphine-enhanced NMDAR phosphorylation, synaptic trafficking of α2δ-1–bound NMDARs, and NMDAR hyperactivity in the spinal cord. Furthermore, pharmacological inhibition of BRAF or MEK, or Braf deletion in DRG neurons, enhanced morphine analgesia while mitigated morphine-induced hyperalgesia and tolerance. These findings identify BRAF overactivity at nociceptor central terminals as a key mediator of opioid-induced NMDAR hyperactivity. Clinically approved BRAF inhibitors could be repurposed to enhance opioid analgesia while minimizing adverse effects.

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