NMDA Receptor Activation Underlies the Loss of Spinal Dorsal Horn Neurons and the Transition to Persistent Pain after Peripheral Nerve Injury

Cell Rep. 2018 May 29;23(9):2678-2689. doi: 10.1016/j.celrep.2018.04.107.


Peripheral nerve lesions provoke apoptosis in the dorsal horn of the spinal cord. The cause of cell death, the involvement of neurons, and the relevance for the processing of somatosensory information are controversial. Here, we demonstrate in a mouse model of sciatic nerve injury that glutamate-induced neurodegeneration and loss of γ-aminobutyric acid (GABA)ergic interneurons in the superficial dorsal horn promote the transition from acute to chronic neuropathic pain. Conditional deletion of Grin1, the essential subunit of N-methyl-d-aspartate-type glutamate receptors (NMDARs), protects dorsal horn neurons from excitotoxicity and preserves GABAergic inhibition. Mice deficient in functional NMDARs exhibit normal nociceptive responses and acute pain after nerve injury, but this initial increase in pain sensitivity is reversible. Eliminating NMDARs fully prevents persistent pain-like behavior. Reduced pain in mice lacking proapoptotic Bax confirmed the significance of neurodegeneration. We conclude that NMDAR-mediated neuron death contributes to the development of chronic neuropathic pain.

Keywords: NMDA receptor; chronic pain; disinhibition; dorsal horn; excitotoxicity; nerve injury; neuropathic pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Survival
  • Chronic Pain / etiology
  • Chronic Pain / pathology
  • Chronic Pain / physiopathology
  • Down-Regulation
  • Gene Deletion
  • Glutamates / metabolism
  • Male
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism*
  • Neural Inhibition
  • Neuralgia / etiology*
  • Neuralgia / pathology
  • Neuralgia / physiopathology
  • Neuroprotection
  • Peripheral Nerve Injuries / complications*
  • Peripheral Nerve Injuries / physiopathology
  • Posterior Horn Cells / metabolism*
  • Posterior Horn Cells / pathology*
  • Protein Transport
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction
  • Synaptic Transmission
  • bcl-2-Associated X Protein / deficiency
  • bcl-2-Associated X Protein / metabolism
  • gamma-Aminobutyric Acid / biosynthesis


  • Glutamates
  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • bcl-2-Associated X Protein
  • gamma-Aminobutyric Acid