Macrophage-Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats

PLoS One. 2016 Apr 12;11(4):e0153375. doi: 10.1371/journal.pone.0153375. eCollection 2016.


Peripheral nerve injury induces proliferation of microglia in the spinal cord, which can contribute to neuropathic pain conditions. However, candidate molecules for proliferation of spinal microglia after injury in rats remain unclear. We focused on the colony-stimulating factors (CSFs) and interleukin-34 (IL-34) that are involved in the proliferation of the mononuclear phagocyte lineage. We examined the expression of mRNAs for macrophage-CSF (M-CSF), granulocyte macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and IL-34 in the dorsal root ganglion (DRG) and spinal cord after spared nerve injury (SNI) in rats. RT-PCR and in situ hybridization revealed that M-CSF and IL-34, but not GM- or G-CSF, mRNAs were constitutively expressed in the DRG, and M-CSF robustly increased in injured-DRG neurons. M-CSF receptor mRNA was expressed in naive rats and increased in spinal microglia following SNI. Intrathecal injection of M-CSF receptor inhibitor partially but significantly reversed the proliferation of spinal microglia and in early phase of neuropathic pain induced by SNI. Furthermore, intrathecal injection of recombinant M-CSF induced microglial proliferation and mechanical allodynia. Here, we demonstrate that M-CSF is a candidate molecule derived from primary afferents that induces proliferation of microglia in the spinal cord and leads to induction of neuropathic pain after peripheral nerve injury in rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / physiology*
  • Ganglia, Spinal / metabolism
  • Hyperalgesia / metabolism
  • Interleukins / metabolism
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Male
  • Microglia / metabolism*
  • Neuralgia / metabolism*
  • Neurons / metabolism
  • Peripheral Nerve Injuries / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Spinal Cord / metabolism*


  • Interleukins
  • RNA, Messenger
  • interleukin-34, mouse
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor

Grants and funding

This work was supported in part by MEXT-supported Program for the Strategic Research Foundation at Private Universities (Grant #: 20451200) to KN from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT; This work was also supported by the Grants-in-Aid for Researchers Hyogo College of Medicine 2014-15 ( to KO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.