Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

Cell Rep. 2019 Jun 25;27(13):3844-3859.e6. doi: 10.1016/j.celrep.2019.05.087.


Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.

Keywords: brain-derived neurotrophic factor; calcitonin gene-related peptide; chronic pain; colony-stimulating factor 1; high-frequency stimulation; long-term potentiation; microglia.

Publication types

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

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / metabolism
  • Chronic Pain / genetics
  • Chronic Pain / metabolism*
  • Chronic Pain / pathology
  • Long-Term Potentiation*
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Neuronal Plasticity*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spinal Cord Dorsal Horn / metabolism*
  • Spinal Cord Dorsal Horn / pathology


  • Receptors, N-Methyl-D-Aspartate
  • Calcitonin Gene-Related Peptide