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Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit
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Edité par CCSD ; Nature Publishing Group -
International audience. Zinc is abundant in the central nervous system and regulates pain, but underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+-NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo, and identify a novel mechanism in pain processing that relies on NR2A NMDA receptors. The study also provides a molecular basis for pain-relieving effects of dietary zinc supplementation.
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