Glutamatergic neurons and myeloid cells in the anterior cingulate cortex mediate secondary hyperalgesia in chronic joint inflammatory pain

Pan, Tingting; Gao, Wei; Song, Zi-hua; Long, Dan-dan; Cao, Peng; Hu, Rui; Chen, Danyang; Zhou, Wenjie; Jin, Yan; Hu, Shanshan; Wei, Wei; Chai, Xiangping; Zhang, Zhi; Wang, Di

doi:10.1016/j.bbi.2021.12.021

Cited by 7 publications

(12 citation statements)

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“…In human studies, magnetic resonance imaging (MRI) has shown that the ACC is the most consistently activated region in patients with chronic pain [ 18 ]. Consistent with brain imaging data, the inhibition of hyperexcitable pyramidal neurons in the ACC has been reported to produce analgesia in experimental rodent models of inflammatory and neuropathic pain [ 19 , 20 ]. The central mechanism underlying chronic pain is usually linked to microglial activation at both spinal and supraspinal sites (including the ACC).…”

Section: Introductionmentioning

confidence: 63%

“…The central mechanism underlying chronic pain is usually linked to microglial activation at both spinal and supraspinal sites (including the ACC). Our [ 19 ] and other works [ 21 – 23 ] indicated that reactive microglia in the ACC, in line with neuronal hyperexcitability, contributed to central neuroadaptation in chronic painful conditions, although the mechanistic details of the reciprocal interactions between neurons and microglia are not well elucidated. In particular, the ACC is also involved in reward processing and addiction.…”

Section: Introductionmentioning

confidence: 85%

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Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain

Long

Zhang

Liu

et al. 2023

J Neuroinflammation

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Background Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice. Methods We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons. Results Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells. Conclusion Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 85%

Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain

Long

Zhang

Liu

et al. 2023

J Neuroinflammation

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“…Given that the hippocampus and prefrontal cortex are the two most vulnerable areas in neurocognitive dysfunction, we selected those two areas throughout the following study. To determine whether microglia were activated in response to cotreatment with LPS/MV, we performed morphological reconstruction of microglia at consecutive time points by using Iba1-staining and further assessed the temporal changes in processes in branch endpoints and length, which is known to correlate well with reactive microglial status (Cao et al 2021 ; Pan et al 2022 ). Experimental studies previously have shown that microglia were moderately active within hours after a single challenge with LPS, reaching their profound activation state after 8 h to 2 days and subsequently returning to their normal surveilling state after 7 days (Hoogland et al 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…Further analyses, such as analysis of fluorescence intensity and colocalization, were conducted using ImageJ software (Fiji edition, NIH). All the experimental details are described elsewhere (Pan et al 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…For morphometric analysis, as mentioned previously (Pan et al 2022 ), confocal images of Iba1-positive cells were visualized and acquired by a confocal laser-scanning microscope (Carl Zeiss LSM880, Germany) with a 40 × objective at 30-μm intervals along the z-axis. We opened the confocal Z-stacks image file and selected “Add New Filaments | Create | Calculate Diameter of Filaments from Image”.…”

Section: Methodsmentioning

confidence: 99%

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Angiotensin Type 2 Receptor Pharmacological Agonist Relieves Neurocognitive Deficits via Reducing Neuroinflammation and Microglial Engulfment of Dendritic Spines

Shen

Chen

Lou

et al. 2022

J Neuroimmune Pharmacol

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Mechanically ventilated patients suffering critical illness are at high risk of developing neurocognitive impairments. Angiotensin type 2 receptor (AGTR2) has been demonstrated to be anti-inflammatory and neuroprotective. The present study thus aimed to investigate whether AGTR2 can alleviate cerebral dysfunction in mice subjected to cochallenge with lipopolysaccharide (LPS) and mechanical ventilation (MV), and to reveal the underlying mechanism. We utilized a mice model that received a single injection of LPS (1 mg/kg, intraperitoneally) followed 2 h later by MV (10 ml/kg, lasting for 2 h). Pretreatment with the AGTR2 pharmacological agonist C21 (0.03, 0.3, and 3 mg/kg, intraperitoneally, once daily, lasting for 10 days). Locomotor activity and behavioral deficits were evaluated 24 h post-MV by open-field and fear-condition tests. Brain hippocampus and prefrontal cortex tissues were collected for immunofluorescence staining and western blotting to evaluate the resulting impacts on microglia, including morphological traits, functional markers, synaptic engulfment, superoxide production, and signaling molecules. Compared with vehicle-control, pre-administrated C21 reduced the branch endpoints and length of microglia processes in a dose-dependent manner in mice subjected to LPS/MV. The neuroprotective effect of AGTR2 was behaviorally confirmed by the improvement of memory decline in LPS/MV-treated mice following C21 pretreatment. In addition to morphological alterations, C21 reduced microglial functional markers and reduced microglial-dendrite contact and microglial engulfment of synaptic protein markers. In terms of the underlying molecular mechanism, AGTR2 stimulation by C21 leads to activation of protein phosphatase 2A, which subsequently mitigates microglial PKCδ and NF-κB activation, and inhibites NOX2-derived ROS production. The AGTR2 agonist C21 alleviates behavioral deficits in those mice subjected to LPS/MV, via mechanisms that involve reactive microglia and abnormal synaptic plasticity in NOX2-derived ROS and the PKCδ-NFκB pathway. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11481-022-10054-7.

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Chronic nicotine exposure elicits pain hypersensitivity through activation of dopaminergic projections to anterior cingulate cortex

Chen,

Shen,

Zhang

et al. 2024

British Journal of Anaesthesia

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Glutamatergic neurons and myeloid cells in the anterior cingulate cortex mediate secondary hyperalgesia in chronic joint inflammatory pain

Cited by 7 publications

References 72 publications

Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain

Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain

Angiotensin Type 2 Receptor Pharmacological Agonist Relieves Neurocognitive Deficits via Reducing Neuroinflammation and Microglial Engulfment of Dendritic Spines

Chronic nicotine exposure elicits pain hypersensitivity through activation of dopaminergic projections to anterior cingulate cortex

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