A transcriptomic analysis of neuropathic pain in the anterior cingulate cortex after nerve injury

Abstract Background Synaptic mechanisms and neuronal oscillations have been proposed to be responsible for neuropathic pain formation. Many studies have also highlighted the important role of electrical synapses in synaptic plasticity and in neuronal oscillations. Thus, electrical synapses may contribute to neuropathic pain generation. However, previous studies have primarily focused on the role of chemical synapses, while ignoring the role of electrical synapses, in neuropathic pain generation. Methods The authors adopted microinjection, RNA interference techniques, and behavioral tests to verify the link between connexin 36 (Cx36) and neuropathic pain. They also studied the selective Cx36 blocker mefloquine in rat chronic constriction injury and spared nerve injury model of neuropathic pain. Electrophysiologic recordings were used to further confirm the behavioral data. Results The authors found that Cx36, which constitutes the neuron–neuron electrical synapses, was up-regulated in the anterior cingulate cortex after nerve injury (n = 5). Meanwhile, Cx36-mediated neuronal oscillations in the gamma frequency range (30 to 80 Hz) (n = 7 to 8) and the neuronal synaptic transmission (n = 13 to 19) were also enhanced. Neuropathic pain was relieved by disrupting Cx36 function or expression in the anterior cingulate cortex. They also found that mefloquine, which are clinically used for treating malaria, affected gamma oscillations and synaptic plasticity, leading to a sustained pain relief in chronic constriction injury and spared nerve injury models (n = 7 to 12). Conclusion The electrical synapses blocker mefloquine could affect gamma oscillations and synaptic plasticity in the anterior cingulate cortex and relieve neuropathic pain. Cx36 may be a new therapeutic target for treating chronic pain.

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The Effect of Optogenetic Inhibition of the Anterior Cingulate Cortex in Neuropathic Pain Following Sciatic Nerve Injury

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01685-7 ◽

2020 ◽

Author(s):

K. C. Elina ◽

Hyeong Cheol Moon ◽

Jaisan Islam ◽

Hyong Kyu Kim ◽

Young Seok Park

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Anterior Cingulate Cortex ◽

Nerve Injury ◽

Cingulate Cortex ◽

Sciatic Nerve Injury ◽

Anterior Cingulate

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RNA Sequencing of Neuropathic Pain in the Anterior Cingulate Cortex after Nerve Injury

10.21203/rs.3.rs-861152/v1 ◽

2021 ◽

Author(s):

yu zhang ◽

Shiwei Jiang ◽

Fei Liao ◽

Zhifeng Huang ◽

Xin Yang ◽

...

Keyword(s):

Neuropathic Pain ◽

Anterior Cingulate Cortex ◽

Rna Sequencing ◽

Nerve Injury ◽

Pathological Condition ◽

Interaction Network ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Initial Increase ◽

Sequencing Analysis

Abstract Background: Neuropathic pain is a troublesome pathological condition without suitable treatments. Anterior Cingulate Cortex (ACC) is a core brain region to process pain emotion. In this study, we performed RNA sequencing analysis to reveal transcriptomic profiles of the ACC in a rat chronic constriction injury (CCI) model.Results: A total of 1628 differentially expressed genes (DEGs) were identified by comparing the sham-operated rats and rats of 12 hours, 1, 3, 7 and 14 days after surgery, respectively. Most of the DEGs were involved in inflammatory and immune process. Although these inflammatory-related DEGs were generally increased after CCI, they demonstrated different kinetics in time-series expression with the development of neuropathic pain affection. Specifically, the expression of Ccl5 , Cxcl9 and Cxcl13 were kept going up after CCI, indicating a potentially effect of these genes on initiation and maintenance of neuropathic pain affection. The expression of Ccl2 , Ccl3 , Ccl4 , Ccl6 and Ccl7 were initially upregulated at 12 hours after CCI and then they fell back after that. Similarly, the expression of Rac2 , Cd68 , Icam-1 , Ptprc , Itgb2 , Fcgr2b were rised at 12 hours and 1 day, but fell back at 3 days after CCI. However, the expression of all of the above two clusters of genes were increased again at 7 days after CCI, when the neuropathic pain affection was developed. The initial increase of these genes may indicate an early response of ACC to nerve injury, whereas the later increase of these genes may indicate their involvement in the developing of neuropathic pain affection. Gene Ontology analysis, KEGG pathway enrichment and interaction network analysis further showed a high connectivity degree among these chemokine targeting genes. Similar expressional changes of these genes were also found in the rat spinal dorsal taking charge of the processing of nociception.Conclusions: Our results indicate chemokines and their targeting genes in ACC may be differentially involved in the initiation and maintenance of neuropathic pain affection. These genes could be the target not only the nociception but also the pain affection subsequent to nerve injury.

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Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with neuropathic pain

10.1101/2021.09.29.462423 ◽

2021 ◽

Author(s):

Stephanie Shiers ◽

Hajira Elahi ◽

Stephanie Hennen ◽

Theodore J Price

Keyword(s):

Neuropathic Pain ◽

Animal Models ◽

Mrna Expression ◽

Anterior Cingulate Cortex ◽

Nerve Injury ◽

Visceral Pain ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Mechanical Hypersensitivity

AbstractThe anterior cingulate cortex (ACC) is a critical region of the brain for the emotional and affective components of pain in rodents and humans. Hyperactivity in this region has been observed in neuropathic pain states in both patients and animal models and ablation of this region from cingulotomy, or inhibition with genetics or pharmacology can diminish pain and anxiety. Two adenylyl cyclases (AC), AC1 and AC8 play an important role in regulating nociception and anxiety-like behaviors through an action in the ACC, as genetic and pharmacological targeting of these enzymes reduces mechanical hypersensitivity and anxietylike behavior, respectively. However, the distribution of these ACs in the ACC has not been studied in the context of neuropathic pain. To address this gap in knowledge, we conducted RNAscope in situ hybridization to assess AC1 and AC8 mRNA distribution in mice with spared nerve injury (SNI). Given the key role of AC1 in nociception in neuropathic, inflammatory and visceral pain animal models, we hypothesized that AC1 would be upregulated in the ACC of mice following nerve injury. This hypothesis was also founded on data showing increased AC1 expression in the ACC of mice with zymosan-induced visceral inflammation. We found that AC1 and AC8 are widely expressed in many regions of the mouse brain including the hippocampus, ACC, medial prefrontal cortex and midbrain regions, but AC1 is more highly expressed. Contrary to our hypothesis, SNI causes an increase in AC8 mRNA expression in NMDAR-2B (Nr2b) positive neurons in the contralateral ACC but does not affect AC1 mRNA expression. Our findings show that changes in Adcy1 mRNA expression in the ACC are insufficient to explain the important role of this AC in mechanical hypersensitivity in mice following nerve injury and suggest a potential unappreciated role of AC8 in regulation of ACC synaptic changes after nerve injury.

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