Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit

Chihiro Nozaki, Angela Maria Vergnano, Dominique Filliol, Abdel Mouttalib Ouagazzal, Anne Le Goff, Stéphanie Carvalho, David Reiss, Claire Gaveriaux-Ruff, Jacques Neyton, Pierre Paoletti, Brigitte L. Kieffer

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

Zinc is abundant in the central nervous system and regulates pain, but the 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 the 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 new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.

Original languageEnglish
Pages (from-to)1017-1022
Number of pages6
JournalNature Neuroscience
Volume14
Issue number8
DOIs
Publication statusPublished - 2011 Aug

ASJC Scopus subject areas

  • Neuroscience(all)

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