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

Chihiro Nozaki (1) , Angela Maria Maria Vergnano (1) , Dominique Filliol (1) , Abdel-Mouttalib Ouagazzal (1) , Anna Le Goff (1) , Stéphanie Carvalho (1) , David Reiss (1) , Claire Gavériaux-Ruff (1) , Jacques Neyton (1) , Pierre Paoletti (1) , Brigitte L Kieffer (1)

1 Section Neuroscience

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.

Mots clés: Pain; Receptors; Synaptic Transmission; Neurophysiology; Neuroscience; Molecular biology

Chihiro Nozaki, Angela Maria Maria Vergnano, Dominique Filliol, Abdel-Mouttalib Ouagazzal, Anna Le Goff, et al.. Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nature Neuroscience, 2011, ⟨10.1038/nn.2844⟩. ⟨hal-00655884⟩