TY - JOUR
T1 - Microglia promote increased pain behavior through enhanced inflammation in the spinal cord during repeated social defeat stress
AU - Sawicki, Caroline M.
AU - Kim, January K.
AU - Weber, Michael D.
AU - Faw, Timothy D.
AU - McKim, Daniel B.
AU - Madalena, Kathryn M.
AU - Lerch, Jessica K.
AU - Basso, D. Michele
AU - Humeidan, Michelle L.
AU - Godbout, Jonathan P.
AU - Sheridan, John F.
N1 - Publisher Copyright:
© 2019 the authors.
PY - 2019/2/13
Y1 - 2019/2/13
N2 - 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.
AB - 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.
KW - Allodynia
KW - Cytokines
KW - Microglia
KW - Repeated social defeat
KW - Stress
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U2 - 10.1523/JNEUROSCI.2785-18.2018
DO - 10.1523/JNEUROSCI.2785-18.2018
M3 - Article
C2 - 30559153
AN - SCOPUS:85061489701
SN - 0270-6474
VL - 39
SP - 1139
EP - 1149
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -