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However, repeated exposure to opioids leads to tolerance, and underlying mechanisms remain elusive. The present study demonstrates that EphB1 receptors play an important role in opioid antinociception through orchestrating \u00b5\u2010opioid receptor (MOR) trafficking. Morphine administration activates EphB1 receptors in the dorsal root ganglion (DRG) and the spinal cord. Deletion of EphB1 receptors in DRG neurons or vesicular glutamate transporter 2 (Vglut2)\u2010expressing neurons in the spinal dorsal horn (DH) augments morphine antinociception. MOR and EphB1 receptors are co\u2010expressed in the somata and axons of DRG neurons and DH Vglut2\n                    <jats:sup>+<\/jats:sup>\n                    neurons. Deletion of EphB1 receptors in DRG neurons increases opioid\u2010induced suppression of calcium currents, and ablation of EphB1 receptors in Vglut2\n                    <jats:sup>+<\/jats:sup>\n                    neurons enhances opioid\u2010induced inhibition of excitatory synaptic transmission and induction of outward currents in Vglut2\n                    <jats:sup>+<\/jats:sup>\n                    DH neurons. Mechanistically, EphB1 receptors form a complex with MOR and G protein\u2010coupled receptor kinase 2 (GRK2) and regulate GRK2\u2010mediated phosphorylation of MOR at Ser\n                    <jats:sup>375<\/jats:sup>\n                    , thus controlling MOR internalization. These findings support the idea that activation of EphB1 receptors may facilitate the development of opioid tolerance through regulating MOR.\n                  <\/jats:p>","DOI":"10.1002\/advs.78099","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:42:00Z","timestamp":1790829720000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EphB1 Receptor Blockade Augments Morphine Antinociception via Inhibiting GRK2\u2010Mediated \u00b5\u2010Opioid Receptor Internalization"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2228-3079","authenticated-orcid":false,"given":"Bo","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Medical Neuroscience School of Medicine Southern University of Science and Technology  Shenzhen China"},{"name":"SUSTech Center for Pain Medicine School of Medicine Southern University of Science and Technology  Shenzhen 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