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Optogenetic activation of spinal microglia triggers chronic pain in mice
Min-Hee Yi1, Yong U Liu1, Anthony D Umpierre1
1Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
Abstract:
Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1β production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.
Insights
Activating spinal microglia optogenetically is sufficient to cause chronic pain. This process involves increased neuronal activity and interleukin-1β signaling, highlighting microglia
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Spinal microglia are implicated in pain signaling following nerve injury.
- Direct evidence for microglial activation sufficiency in inducing chronic pain is lacking.
Purpose of the Study:
- To investigate if selective in vivo optogenetic activation of spinal microglia can induce chronic pain phenotypes.
- To elucidate the molecular mechanisms underlying microglial activation-induced pain.
Main Methods:
- Utilized CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice for inducible and specific microglial expression of red-activated channelrhodopsin (ReaChR).
- Employed optogenetic stimulation with red light to activate spinal microglia in vivo.
- Assessed pain hypersensitivity, neuronal activity (c-Fos expression), C-fiber responses, and IL-1β production.
- Administered IL-1 receptor antagonist (IL-1ra) to evaluate its effect on induced pain.
Main Results:
- Optogenetic activation of microglial ReaChR induced inward currents and membrane depolarization.
- In vivo activation triggered chronic pain hypersensitivity in both male and female mice.
- Microglial activation led to increased neuronal c-Fos expression and enhanced C-fiber activity.
- ReaChR activation induced a reactive microglial phenotype with elevated IL-1β, mediated by inflammasome activation and calcium influx.
- IL-1ra treatment reversed the pain hypersensitivity and neuronal hyperactivity.
Conclusions:
- Optogenetic activation of spinal microglia is sufficient to induce chronic pain phenotypes.
- Microglial activation increases neuronal activity, likely through IL-1β signaling pathways.
- This study provides direct evidence for the causal role of spinal microglia in chronic pain development.
