Spinal Cord Stimulation Alleviates Neuropathic Pain by Attenuating Microglial Activation via Reducing Colony-Stimulating Factor 1 Levels in the Spinal Cord in a Rat Model of Chronic Constriction Injury

Anesth Analg. 2022 Jul 1;135(1):178-190. doi: 10.1213/ANE.0000000000006016. Epub 2022 Apr 4.


Background: Spinal cord stimulation (SCS) is an emerging, minimally invasive procedure used to treat patients with intractable chronic pain conditions. Although several signaling pathways have been proposed to account for SCS-mediated pain relief, the precise mechanisms remain poorly understood. Recent evidence reveals that injured sensory neuron-derived colony-stimulating factor 1 (CSF1) induces microglial activation in the spinal cord, contributing to the development of neuropathic pain (NP). Here, we tested the hypothesis that SCS relieves pain in a rat model of chronic constriction injury (CCI) by attenuating microglial activation via blocking CSF1 to the spinal cord.

Methods: Sprague-Dawley rats underwent sciatic nerve ligation to induce CCI and were implanted with an epidural SCS lead. SCS was delivered 6 hours per day for 5 days. Some rats received a once-daily intrathecal injection of CSF1 for 3 days during SCS.

Results: Compared with naive rats, CCI rats had a marked decrease in the mechanical withdrawal threshold of the paw, along with increased microglial activation and augmented CSF1 levels in the spinal dorsal horn and dorsal root ganglion, as measured by immunofluorescence or Western blotting. SCS significantly increased the mechanical withdrawal threshold and attenuated microglial activation in the spinal dorsal horn in CCI rats, which were associated with reductions in CSF1 levels in the spinal dorsal horn and dorsal roots but not dorsal root ganglion. Moreover, intrathecal injection of CSF1 completely abolished SCS-induced changes in the mechanical withdrawal threshold and activation of microglia in the spinal dorsal horn in CCI rats.

Conclusions: SCS reduces microglial activation in the spinal cord and alleviates chronic NP, at least in part by inhibiting the release of CSF1 from the dorsal root ganglion ipsilateral to nerve injury.

MeSH terms

  • Animals
  • Constriction
  • Humans
  • Hyperalgesia / metabolism
  • Hyperalgesia / therapy
  • Macrophage Colony-Stimulating Factor / metabolism
  • Microglia / metabolism
  • Neuralgia* / metabolism
  • Neuralgia* / therapy
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / metabolism
  • Spinal Cord Dorsal Horn / metabolism
  • Spinal Cord Stimulation*


  • Macrophage Colony-Stimulating Factor