Microglial activation in the trigeminal spinal subnucleus interpolaris/caudalis modulates orofacial incisional mechanical pain hypersensitivity associated with orofacial injury in infancy

Optogenetic activation of spinal microglia triggers chronic pain in mice

PLoS Biology ◽

10.1371/journal.pbio.3001154 ◽

2021 ◽

Vol 19 (3) ◽

pp. e3001154

Author(s):

Min-Hee Yi ◽

Yong U. Liu ◽

Anthony D. Umpierre ◽

Tingjun Chen ◽

Yanlu Ying ◽

...

Keyword(s):

Chronic Pain ◽

Microglial Activation ◽

Red Light ◽

Inflammasome Activation ◽

Pain Hypersensitivity ◽

Microglial Phenotype ◽

C Fiber ◽

Inward Currents ◽

Calcium Elevation

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been any 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.

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Optogenetic activation of spinal microglia triggers chronic pain in mice

10.1101/2020.07.19.211250 ◽

2020 ◽

Author(s):

Min-Hee Yi ◽

Yong U. Liu ◽

Anthony D. Umpierre ◽

Tingjun Chen ◽

Yanlu Ying ◽

...

Keyword(s):

Chronic Pain ◽

Peripheral Nerve Injury ◽

Microglial Activation ◽

Direct Evidence ◽

Red Light ◽

Pain Hypersensitivity ◽

Microglial Phenotype ◽

C Fiber ◽

Inward Currents

AbstractSpinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in neuropathic pain. However, there has not been any direct evidence showing 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 lasting for 5-7 days. In addition, activation of microglial ReaChR upregulated neuronal c-fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased IL-1β production. IL-1 receptor antagonist 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.

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Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice

eLife ◽

10.7554/elife.69056 ◽

2021 ◽

Vol 10 ◽

Author(s):

Julia Kuhn ◽

Ilia D Vainchtein ◽

Joao M Braz ◽

Katherine Hamel ◽

Mollie Bernstein ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Nerve Injury ◽

Sensory Neurons ◽

Microglial Activation ◽

Transcriptional Profiling ◽

Intrathecal Administration ◽

Pain Hypersensitivity ◽

Female Mice ◽

Stimulating Factor

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice. Transcriptional profiling and morphologic analyses after intrathecal CSF1 showed robust immune activation in male but not female microglia. CSF1 also induced marked expansion of lymphocytes within the spinal cord meninges, with preferential expansion of regulatory T-cells (Tregs) in female mice. Consistent with the hypothesis that Tregs actively suppress microglial activation in females, Treg deficient (Foxp3DTR) female mice showed increased CSF1-induced microglial activation and pain hypersensitivity equivalent to males. We conclude that sexual dimorphism in the contribution of microglia to pain results from Treg-mediated suppression of microglial activation and pain hypersensitivity in female mice.

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Pain hypersensitivity in patients with functional gastrointestinal disorders: A gastrointestinal specific defect or a systemic general condition?

Gastroenterology ◽

10.1016/s0016-5085(01)83164-4 ◽

2001 ◽

Vol 120 (5) ◽

pp. A636-A637

Author(s):

M BOUIN ◽

P MEUNIER ◽

M RIBERDY ◽

M BOIVIN ◽

V PLOURDE ◽

...

Keyword(s):

General Condition ◽

Functional Gastrointestinal Disorders ◽

Gastrointestinal Disorders ◽

Pain Hypersensitivity

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Inflammational Animal Models for Schizophrenia

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000216 ◽

2015 ◽

Vol 223 (3) ◽

pp. 157-164 ◽

Cited By ~ 1

Author(s):

Georg Juckel

Keyword(s):

Animal Model ◽

Animal Models ◽

Immune Activation ◽

Microglial Activation ◽

Treatment Options ◽

Early Adulthood ◽

Brain Regions ◽

Synaptic Connections ◽

Preventive Interventions ◽

Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

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