Topography of microglial activation in sensory- and affect-related brain regions in chronic pain

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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A38 TRPV1 VISCERAL AFFERENTS CONTROL CENTRAL SENSITIZATION IN IBD

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.036 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 278-279

Author(s):

M Defaye ◽

N Abdullah ◽

M Iftinca ◽

C Altier

Keyword(s):

Chronic Pain ◽

Central Sensitization ◽

Microglial Activation ◽

Visceral Pain ◽

Purinergic Signaling ◽

Designer Drugs ◽

Visceral Afferents ◽

Peripheral Sensitization ◽

Specific Expression

Abstract Background Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease, suggesting a high level of plasticity in nociceptive circuits during acute phases. The establishment of chronic visceral pain results from neuroplasticity in nociceptors first, then along the entire neural axis, wherein microglia, the resident immune cells of the central nervous system, are critically involved. Our lab has shown that spinal microglia were key in controlling chronic pain state in IBD. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown. Aims To investigate the role of TRPV1+ visceral afferents in microglial activation and chronic visceral pain. Methods We generated DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice in which TRPV1 sensory neurons can be inhibited (TRPV1-hM4Di) or activated (TRPV1-hM3Dq) in a time and tissue specific manner using the inert ligand Clozapine-N-Oxide (CNO). To test the inhibition of TRPV1 neurons in DSS-induced colitis, TRPV1-hM4Di mice were treated with DSS 2.5% or water for 7 days and received vehicle or CNO i.p. injection twice daily. To activate TRPV1 visceral afferents, TRPV1-hM3Dq mice received vehicle or CNO daily for 7 days, by oral gavage. After 7 days of treatment, visceral pain was evaluated by colorectal distension and spinal cords tissues were harvested to measure microglial activation. Results Our data validated the nociceptor specific expression and function of the DREADD in TRPV1-Cre mice. Inhibition of TRPV1 visceral afferents in DSS TRPV1-hM4Di mice was able to prevent the colitis-induced microglial activation and thus reduce visceral hypersensitivity. In contrast, activation of TRPV1 visceral afferents in TRPV1-hM3Dq mice was sufficient to drive microglial activation in the absence of colitis. Analysis of the proalgesic mediators derived from activated TRPV1-hM3Dq neurons identified ATP as a key factor of microglial activation. Conclusions Overall, these data provide novel insights into the mechanistic understanding of the gut/brain axis in chronic visceral pain and suggest a role of purinergic signaling that could be harnessed for testing effective therapeutic approaches to relieve pain in IBD patients. Funding Agencies CCCACHRI (Alberta Children’s Hospital Research Institute) and CSM (Cumming School of Medicine) postdoctoral fellowship

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Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

Molecular Pain ◽

10.1177/1744806921990934 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199093

Author(s):

Dan-jie Su ◽

Long-fei Li ◽

Sai-ying Wang ◽

Qi Yang ◽

Yu-jing Wu ◽

...

Keyword(s):

Chronic Pain ◽

Mouse Model ◽

Anterior Cingulate Cortex ◽

Analgesic Effect ◽

Microglial Activation ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

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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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The link between chronic pain and Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-019-1608-z ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 13

Author(s):

Song Cao ◽

Daniel W. Fisher ◽

Tain Yu ◽

Hongxin Dong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Chronic Pain ◽

Animal Studies ◽

Microglial Activation ◽

The Elderly ◽

Therapeutic Interventions ◽

Affective Component ◽

Inflammatory Activation ◽

Improve Patient

Abstract Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer’s disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.

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Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

NeuroImage Clinical ◽

10.1016/j.nicl.2015.09.012 ◽

2015 ◽

Vol 9 ◽

pp. 430-435 ◽

Cited By ~ 37

Author(s):

Natalia Egorova ◽

Randy L. Gollub ◽

Jian Kong

Keyword(s):

Chronic Pain ◽

Brain Regions ◽

Placebo Acupuncture

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In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1612-0 ◽

2010 ◽

Vol 38 (2) ◽

pp. 343-351 ◽

Cited By ~ 97

Author(s):

Masamichi Yokokura ◽

Norio Mori ◽

Shunsuke Yagi ◽

Etsuji Yoshikawa ◽

Mitsuru Kikuchi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Brain Regions ◽

Amyloid Deposits

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The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

10.1101/2020.10.26.355529 ◽

2020 ◽

Author(s):

Elena Makovac ◽

Alessandra Venezia ◽

David Hohenschurz-Schmidt ◽

Ottavia Dipasquale ◽

Jade B Jackson ◽

...

Keyword(s):

Chronic Pain ◽

Functional Connectivity ◽

Pain Control ◽

Brain Regions ◽

Pain Modulation ◽

Autonomic Reactivity ◽

Pain Mechanisms ◽

Cold Pain ◽

Periaqueductal Grey ◽

Descending Pain Modulation

AbstractThere is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored.Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded.Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes.Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.

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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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Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice

10.21203/rs.2.22927/v1 ◽

2020 ◽

Author(s):

Hui-Ting Huang ◽

Po-See Chen ◽

Yu-Ming Kuo ◽

Shun-Fen Tzeng

Keyword(s):

Exploratory Behavior ◽

Microglial Activation ◽

Basolateral Amygdala ◽

Brain Regions ◽

Anterior Cingulate ◽

Mrna Levels ◽

Morphological Examination ◽

Intermittent Exposure ◽

Immune Challenges ◽

Hypothalamic Tissue

Abstract Background Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. Methods In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. Results The plasma levels and hypothalamic mRNA levels of IL-1b and TNF-a were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the NAc and insula. Moreover, microglial activation in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice. Conclusions Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced exploratory behavior. Our findings suggest that intermittent acute peripheral immune challenges and chronic HFD intake can cause microglia to modify the microenvironment and further modify animal behaviors.

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