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

Chihiro Nozaki*, Angela Vergnano*, Dominique Filliol, Abdel Ouagazzal, Anne Le Goff, Stéphanie Carvalho, David Reiss, Claire Gaveriaux-Ruff, Jacques Neyton, Pierre Paoletti# and Brigitte Kieffer#
*co-first author
#co-senior author

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 provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.

Nat Neurosci. 2011 Jul 3;14(8):1017-22.