{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:01:12Z","timestamp":1792130472516,"version":"4.4.0"},"reference-count":78,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["DA041711"],"award-info":[{"award-number":["DA041711"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>\n                    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 \u03b12\u03b4-1\u2013bound NMDARs. Vemurafenib also abolished morphine-induced presynaptic NMDAR hyperactivity in spinal dorsal horn neurons. Correspondingly, conditional\n                    <jats:italic>Braf<\/jats:italic>\n                    knockout in DRG neurons normalized morphine-enhanced NMDAR phosphorylation, synaptic trafficking of \u03b12\u03b4-1\u2013bound NMDARs, and NMDAR hyperactivity in the spinal cord. Furthermore, pharmacological inhibition of BRAF or MEK, or\n                    <jats:italic>Braf<\/jats:italic>\n                    deletion in DRG neurons, enhanced morphine analgesia while mitigating 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.\n                  <\/jats:p>","DOI":"10.1172\/jci201808","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T16:00:18Z","timestamp":1784044818000},"source":"Crossref","is-referenced-by-count":1,"title":["Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor 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