Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Yi, Min; Liu, Yong; Liu, Kevin; Chen, Tingjun; Bosco, Dale B.; Zheng, Jiaying; Xie, Manling; Zhou, Lijun; Qu, Wenchun; Wu, Long

doi:10.1016/j.bbi.2020.11.030

Cited by 97 publications

(82 citation statements)

References 52 publications

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“…It is worth noting that Gq- and Gi-DREADD can bidirectionally modulate microglial activity in vivo, and are useful to explore the pathophysiological roles of spinal microglia. However, in contrast to our results, Yi et al demonstrated that the activation of Gi-DREADD in spinal microglia attenuated NP in both male and female mice [ 59 ]. Since there is some discrepancy among the research communities, further evidence is required to fully understand the sex-dependent roles of spinal microglia in pain regulation.…”

Section: Discussioncontrasting

confidence: 99%

“…Similarly, Grace et al demonstrated that the induction of Gi-DREADD in spinal microglia temporarily relieved mechanical allodynia after nerve injury in vivo, and attenuated inflammatory responses by lipopolysaccharide treatment in vitro [ 17 ]. Recently, Yi et al also showed that the induction of Gi-DREADD in microglia suppressed microglial activation and pain hypersensitivity after nerve injury [ 59 ]. These lines of evidence share a common view that Gi-DREADD in reactive microglia might attenuate pain hypersensitivity caused by nerve injury.…”

Section: Discussionmentioning

confidence: 99%

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Chemogenetic Activation of CX3CR1-Expressing Spinal Microglia Using Gq-DREADD Elicits Mechanical Allodynia in Male Mice

Saika

Matsuzaki

Kishioka

et al. 2021

Cells

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It is important to investigate the sex-dependent roles of microglia in pain hypersensitivity as reactive microglia within the spinal dorsal horn (DH) have been reported to be pivotal in neuropathic pain induction in male rodents upon nerve injury. Here, we aimed at determining the role of sex differences in the behavioral and functional outcomes of the chemogenetic activation of spinal microglia using Gq-designer receptors exclusively activated by designer drugs (Gq-DREADD) driven by the microglia-specific Cx3cr1 promoter. CAG-LSL-human Gq-coupled M3 muscarinic receptors (hM3Dq)-DREADD mice were crossed with CX3C chemokine receptor 1 (CX3CR1)-Cre mice, and immunohistochemistry images revealed that hM3Dq was selectively expressed on Iba1+ microglia, but not on astrocytes and neurons. Intrathecal (i.t.) administration of clozapine-N-oxide (CNO) elicited mechanical allodynia exclusively in male mice. Furthermore, the reactive microglia-dominant molecules that contributed to pain hypersensitivity in CX3CR1-hM3Dq were upregulated in mice of both sexes. The degree of upregulation was greater in male than in female mice. Depletion of spinal microglia using pexidartinib (PLX3397), a colony stimulating factor-1 receptor inhibitor, alleviated the male CX3CR1-hM3Dq mice from pain hypersensitivity and compromised the expression of inflammatory molecules. Thus, the chemogenetic activation of spinal microglia resulted in pain hypersensitivity in male mice, suggesting the sex-dependent molecular aspects of spinal microglia in the regulation of pain.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chemogenetic Activation of CX3CR1-Expressing Spinal Microglia Using Gq-DREADD Elicits Mechanical Allodynia in Male Mice

Saika

Matsuzaki

Kishioka

et al. 2021

Cells

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“…In addition, many studies have shown that genetic knockout of microglial signaling molecules or depletion of microglia partially reverse neuropathic pain [6,7], suggesting microglia as a key player in chronic pain pathogenesis. Indeed, chemogenetic activation of microglia is sufficient to trigger pain hypersensitivity [8], while chemogenetic inhibition of microglia attenuates chronic pain in rodents [9,10]. Given the complex interactions between neurons, glia, and immune cells in pain modulation, dissecting the specific role of microglia requires the continuous development of new tools.…”

Section: Introductionmentioning

confidence: 99%

Optogenetic activation of spinal microglia triggers chronic pain in mice

Liu

Umpierre

et al. 2021

PLoS Biol

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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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“…We found that activation of microglia attenuated synaptic transmission and reduced neuroinflammation, synaptic function, and neuralgia. Therefore, chemotherapy offers a potential opportunity to explore microglia function and neuropathic pain treatment [46] Analysis of the keywords with the strongest citation bursts from 2000 to 2019 revealed major hot spots in the field of neuropathic pain rehabilitation (as shown in Figure 6). The top 25 keywords in 2000 included "reflex sympathetic dystrophy," "complex regional pain syndrome," "gabapentin," "diabetic neuropathy," and "neuralgia."…”

Section: Research Hot Spots and Trendsmentioning

confidence: 99%

Global Research on Neuropathic Pain Rehabilitation over the Last 20 Years

2021

Neural Plasticity

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Background. Neuropathic pain has long been a very popular and productive field of clinical research. Neuropathic pain is difficult to cure radically because of its complicated etiology and uncertain pathogenesis. As pain worsens and persists, pain recovery techniques become more important, and medication alone is insufficient. No summary of bibliometric studies on neuropathic pain rehabilitation is yet available. The purpose of the present study is to analyze in a systematic manner the trends of neuropathic pain rehabilitation research over the period of 2000–2019. Methods. Studies related to neuropathic pain rehabilitation and published between January 2000 and December 2019 were obtained from the Science Citation Index-Expanded of Web of Science. No restrictions on language, literature type, or species were established. CiteSpace V and Microsoft Excel were used to capture basic information and highlights in the field. Results. Linear regression analysis showed that the number of publications on neuropathic pain rehabilitation significantly increased over time ( P < 0.001 ). The United States showed absolute strength in terms of number of papers published, influence, and cooperation with other countries. Based on the subject categories of the Web of Science, “Rehabilitation” had the highest number of published papers (446), the highest number of citations (10,954), and the highest number of open-access papers (151); moreover, this category and “Clinical Neurology” had the same H -index (i.e., 52). “Randomized Controlled Trials” revealed the largest cluster in the cocitation map of references. The latest burst keywords included “Exercise” (2014–2019), “Functional Recovery” (2015–2019), and “Questionnaire” (2015–2019). Conclusion. This study provides valuable information for neuropathic pain rehabilitation researchers seeking fresh viewpoints related to collaborators, cooperative institutions, and popular topics in this field. Some new research trends are also highlighted.

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Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Cited by 97 publications

References 52 publications

Chemogenetic Activation of CX3CR1-Expressing Spinal Microglia Using Gq-DREADD Elicits Mechanical Allodynia in Male Mice

Chemogenetic Activation of CX3CR1-Expressing Spinal Microglia Using Gq-DREADD Elicits Mechanical Allodynia in Male Mice

Optogenetic activation of spinal microglia triggers chronic pain in mice

Global Research on Neuropathic Pain Rehabilitation over the Last 20 Years

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