{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:50:07Z","timestamp":1788922207046,"version":"build-2803163510"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"902","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,9,2]]},"abstract":"<jats:p>\n            Opioids relieve pain by activating \u03bc-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein G\u03b1\n            <jats:sub>q<\/jats:sub>\n            in this paradox. Pharmacological inhibition of G\u03b1\n            <jats:sub>q<\/jats:sub>\n            in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced G\u03b1\n            <jats:sub>q<\/jats:sub>\n            coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of G\u03b1\n            <jats:sub>q<\/jats:sub>\n            in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of G\u03b1\n            <jats:sub>q<\/jats:sub>\n            signaling enhanced morphine\u2019s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that G\u03b1\n            <jats:sub>q<\/jats:sub>\n            signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adu8839","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T17:58:47Z","timestamp":1756835927000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["G\u03b1\n            <sub>q<\/sub>\n            signaling in primary sensory neurons shifts opioid analgesia to NMDA receptor\u2013driven tolerance and hyperalgesia"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6304-2713","authenticated-orcid":true,"given":"Daozhong","family":"Jin","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, 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