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Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress.

Publication ,  Journal Article
Sawicki, CM; Kim, JK; Weber, MD; Faw, TD; McKim, DB; Madalena, KM; Lerch, JK; Basso, DM; Humeidan, ML; Godbout, JP; Sheridan, JF
Published in: J Neurosci
February 13, 2019

Clinical studies indicate that psychosocial stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. Here we show that mechanical allodynia in male mice was increased with exposure to RSD. This stress-induced behavior corresponded with increased mRNA expression of several inflammatory genes, including IL-1β, TNF-α, CCL2, and TLR4 in the lumbar spinal cord. While there were several adhesion and chemokine-related genes increased in the lumbar spinal cord after RSD, there was no accumulation of monocytes or neutrophils. Notably, there was evidence of microglial activation selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar cord. Elimination of microglia using the colony stimulating factor 1 receptor antagonist PLX5622 from the brain and spinal cord prevented the development of mechanical allodynia in RSD-exposed mice. Microglial elimination also attenuated RSD-induced IL-1β, CCR2, and TLR4 mRNA expression in the lumbar spinal cord. Together, RSD-induced allodynia was associated with microglia-mediated inflammation within the dorsal horn of the lumbar spinal cord.SIGNIFICANCE STATEMENT Mounting evidence indicates that psychological stress contributes to the onset and progression of adverse nociceptive conditions. We show here that repeated social defeat stress causes increased pain sensitivity due to inflammatory signaling within the nociceptive circuits of the spinal cord. Studies here mechanistically tested the role of microglia in the development of pain by stress. Pharmacological ablation of microglia prevented stress-induced pain sensitivity. These findings demonstrate that microglia are critical mediators in the induction of pain conditions by stress. Moreover, these studies provide a proof of principle that microglia can be targeted as a therapeutic strategy to mitigate adverse pain conditions.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

February 13, 2019

Volume

39

Issue

7

Start / End Page

1139 / 1149

Location

United States

Related Subject Headings

  • Stress, Psychological
  • Spinal Cord Injuries
  • Spinal Cord Diseases
  • Spinal Cord
  • Social Environment
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Organic Chemicals
  • Neurology & Neurosurgery
  • Microglia
  • Mice, Inbred C57BL
 

Citation

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Sawicki, C. M., Kim, J. K., Weber, M. D., Faw, T. D., McKim, D. B., Madalena, K. M., … Sheridan, J. F. (2019). Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. J Neurosci, 39(7), 1139–1149. https://doi.org/10.1523/JNEUROSCI.2785-18.2018
Sawicki, Caroline M., January K. Kim, Michael D. Weber, Timothy D. Faw, Daniel B. McKim, Kathryn M. Madalena, Jessica K. Lerch, et al. “Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress.J Neurosci 39, no. 7 (February 13, 2019): 1139–49. https://doi.org/10.1523/JNEUROSCI.2785-18.2018.
Sawicki CM, Kim JK, Weber MD, Faw TD, McKim DB, Madalena KM, et al. Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. J Neurosci. 2019 Feb 13;39(7):1139–49.
Sawicki, Caroline M., et al. “Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress.J Neurosci, vol. 39, no. 7, Feb. 2019, pp. 1139–49. Pubmed, doi:10.1523/JNEUROSCI.2785-18.2018.
Sawicki CM, Kim JK, Weber MD, Faw TD, McKim DB, Madalena KM, Lerch JK, Basso DM, Humeidan ML, Godbout JP, Sheridan JF. Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. J Neurosci. 2019 Feb 13;39(7):1139–1149.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

February 13, 2019

Volume

39

Issue

7

Start / End Page

1139 / 1149

Location

United States

Related Subject Headings

  • Stress, Psychological
  • Spinal Cord Injuries
  • Spinal Cord Diseases
  • Spinal Cord
  • Social Environment
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Organic Chemicals
  • Neurology & Neurosurgery
  • Microglia
  • Mice, Inbred C57BL