CNS myeloid cells critically regulate heat hyperalgesia
Stefanie Kälin, … , Christian Witzel, Frank L. Heppner
Stefanie Kälin, … , Christian Witzel, Frank L. Heppner
Published April 10, 2018
Citation Information: J Clin Invest. 2018;128(7):2774-2786. https://doi.org/10.1172/JCI95305.
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Research Article Neuroscience

CNS myeloid cells critically regulate heat hyperalgesia

Abstract

Activation of non-neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia-mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b-HSVTK–transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene–related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat.

Authors

Stefanie Kälin, Kelly R. Miller, Roland E. Kälin, Marina Jendrach, Christian Witzel, Frank L. Heppner

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Figure 5

Microglia-depleted mice lack heat hyperalgesia.

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Microglia-depleted mice lack heat hyperalgesia. (A and B) No deficits in...
(A and B) No deficits in the RotaRod or tail-flick test were observed in GCV- or aCSF-treated GFP>WT or GFP>TK animals, or in sham-operated GFP>TK controls several days post pump (dpp) implantation, up to 50 days after PSNL. (C and D) No changes in baseline values were observed before PSNL. Mechanical allodynia and heat hyperalgesia were detectable in GCV-treated GFP>WT (n = 8), aCSF-treated GFP>WT (n = 8), and aCSF-treated GFP>TK (n = 8) animals after PSNL. In GCV-treated GFP>TK mice (n = 8 up to 21 dpi, n = 6 for 35 and 50 dpi), PSNL resulted in a lasting formation of mechanical allodynia, but not heat hyperalgesia. Sham-operated GFP>TK mice (n = 8 up to 7 dpi, n = 5–6 for 14 and 21 dpi, n = 2–4 for 35 and 50 dpi) developed neither mechanical allodynia nor heat hyperalgesia. (E) Increased sensitivity to cold stimuli was only detected after PSNL in GFP>WT (n = 9) and GFP>TK (n = 7 up to 8 dpp, n = 4–6 from 12 dpp onward) mice. (F and G) At long-term repopulation time points, no deficits in the RotaRod or tail-flick test were observed in GFP>WT or GFP>TK mice. (H and I) GCV-treated, long-term repopulated GFP>TK mice (n = 5/genotype) lacked heat hyperalgesia, but developed lasting mechanical allodynia. Error bars indicate the SEM. Linear mixed models with adjustment for multiple testing were used for statistical analysis. In post hoc tests, group differences on days 14 and 50 after PSNL were tested. Adjustment for multiple testing was done within each model using Bonferroni’s correction (A–D). Significant differences were determined for GCV-treated GFP>WT, aCSF-treated GFP>WT, aCSF-treated GFP>TK, and GCV-treated GFP>TK mice versus sham-treated mice (C and D). *P < 0.05, **P < 0.01, and ***P < 0.001, by paired, 2-tailed Student’s t test (E–I).