title: Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit.
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.
authors: Institut de Génétique et Biologie Moléculaire et Cellulaire, Illkirch, France.
authors: Chihiro
authors: C
authors: Nozaki
authors: Angela Maria
authors: AM
authors: Vergnano
authors: Dominique
authors: D
authors: Filliol
authors: Abdel-Mouttalib
authors: AM
authors: Ouagazzal
authors: Anne
authors: A
authors: Le Goff
authors: Stéphanie
authors: S
authors: Carvalho
authors: David
authors: D
authors: Reiss
authors: Claire
authors: C
authors: Gaveriaux-Ruff
authors: Jacques
authors: J
authors: Neyton
authors: Pierre
authors: P
authors: Paoletti
authors: Brigitte L
authors: BL
authors: Kieffer
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018737:Hand Strength / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006639:Histidine / Q000235:genetics; D066298:In Vitro Techniques; D007814:Larva; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D011485:Protein Binding / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D012694:Serine / Q000235:genetics; D012903:Smell / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D018709:Statistics, Nonparametric; D055698:Touch Perception / Q000187:drug effects / Q000235:genetics; D014131:Trace Elements / Q000494:pharmacology* / Q000627:therapeutic use; D014981:Xenopus; D015032:Zinc / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014131:Trace Elements; D012694:Serine; D006639:Histidine; D015032:Zinc