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Published on: January 7, 2019
CNS myeloid cells critically regulate heat hyperalgesia
Stefanie Kälin1, Kelly R Miller1, Roland E Kälin1
1Department of Neuropathology and.
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.
Insights
Peripheral myeloid cells in the central nervous system (CNS) are crucial for processing noxious heat pain. Ablating resident microglia revealed their distinct role in thermal hypersensitivity following nerve injury.
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Microglia activation is implicated in neuropathic pain.
- Previous methods had limitations in studying microglia function post-nerve injury.
Purpose of the Study:
- To investigate microglia-mediated effects in neuropathic pain.
- To selectively ablate resident microglia and observe repopulation by peripheral myeloid cells.
Main Methods:
- Selective ablation of resident microglia using intracerebroventricular ganciclovir in CD11b-HSVTK-transgenic mice.
- Sciatic nerve injury model to induce neuropathic pain.
- Assessment of mechanical and thermal hypersensitivity, and neuronal calcitonin gene-related peptide (CGRP) expression.
Main Results:
- Complete and persistent repopulation of the CNS by peripheral myeloid cells after microglia ablation.
- Absence of thermal hypersensitivity, but normal mechanical sensitivity, in repopulated mice post-nerve injury.
- Diminished neuronal CGRP expression in the spinal cord dorsal horn of repopulated mice.
Conclusions:
- Distinct mechanisms underlie heat and mechanical hypersensitivity.
- Central nervous system myeloid cells play a critical role in facilitating noxious heat pain.
- This study highlights the importance of CNS myeloid cells in pain processing.
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