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.
Authors
Daozhong Jin, Hong Chen, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
- Download (1.18 MB)
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)