Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses

Missig, Galen; Fritsch, Emma L.; Mehta, Niyati; Damon, Miles E.; Jarrell, Erica M.; Bartlett, Andrew A.; Carroll, F. Ivy; Carlezon, William A.

doi:10.1016/j.pbb.2021.173301

Cited by 11 publications

(4 citation statements)

References 43 publications

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“…Additionally, the ability of KOR antagonists—which can mitigate the long-lasting effects of stress on a variety of endpoints including sleep [ 52 , 54 ]—to block CSDS effects on adrenal atrophy but not thymic involution provides insights on the mechanisms by which this class of drugs produce their putative therapeutic effects. One possibility is that KOR antagonists do not block chronic stress effects on immune function; indeed, if anything, KOR antagonists appear to increase pro-inflammatory factors following immune system activation [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

et al. 2022

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Exposure to stress triggers biological changes throughout the body. Accumulating evidence indicates that alterations in immune system function are associated with the development of stress-associated illnesses such as major depressive disorder and post-traumatic stress disorder, increasing interest in identifying immune markers that provide insight into mental health. Recombination events during T-cell receptor rearrangement and T-cell maturation in the thymus produce circular DNA fragments called T-cell receptor excision circles (TRECs) that can be utilized as indicators of thymic function and numbers of newly emigrating T-cells. Given data suggesting that stress affects thymus function, we examined whether blood levels of TRECs might serve as a quantitative peripheral index of cumulative stress exposure and its physiological correlates. We hypothesized that chronic stress exposure would compromise thymus function and produce corresponding decreases in levels of TRECs. In male mice, exposure to chronic social defeat stress (CSDS) produced thymic involution, adrenal hypertrophy, and decreased levels of TRECs in blood. Extending these studies to humans revealed robust inverse correlations between levels of circulating TRECs and childhood emotional and physical abuse. Cell-type specific analyses also revealed associations between TREC levels and blood cell composition, as well as cell-type specific methylation changes in CD4T + and CD8T + cells. Additionally, TREC levels correlated with epigenetic age acceleration, a common biomarker of stress exposure. Our findings demonstrate alignment between findings in mice and humans and suggest that blood-borne TRECs are a translationally-relevant biomarker that correlates with, and provides insight into, the cumulative physiological and immune-related impacts of stress exposure in mammals.

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Section: Discussionmentioning

confidence: 99%

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

et al. 2022

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“…LPS снижает экспрессию КОР. Предполагается, что снижение функции КОР стимулирует продукцию провоспалительных цитокинов в головном мозге преимущественно за счет воздействия на микроглию [36].…”

Section: механизмы нейровоспаления на различных экспериментальных мод...unclassified

“…Учитывая это, есть необходимость в дальнейших исследованиях, чтобы понять существуют ли региональные различия реакции микроглии в ответ на стимуляцию или блокирование КОР. Кроме того, неясно насколько велика роль КОР микроглии в регуляции нейровоспаления, которое, помимо прочего, может также зависеть от влияния циркулирующих провоспалительных цитокинов, высвобождаемых другими иммунными клетками [36]. Немаловажное значение имеют возраст и половая принадлежность особей, которые подвергаются воздействию LPS, поскольку раннее введение LPS может провоцировать (в зависимости от пола) разные реакции в поведении и относительных уровнях экспрессии про-и противовоспалительных факторов [40,41].…”

Section: механизмы нейровоспаления на различных экспериментальных мод...unclassified

Models of neuroinflammation for the assessment of kappa-opioid receptor ligands

Kalitin

Spasov

Mukha

2023

Farm. farmakol. (Pâtigorsk)

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The development of new drugs to combat neuroinflammation is highly relevant as it opens up possibilities for the treatment of a wide range of diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, depression, and others. Kappa-opioid agonists represent a promising class of compounds with а high potential to be used in the treatment of neurological conditions accompanied by neuroinflammation.The aim of the study was to provide a summary of the current strategies employed to evaluate the neurotropic anti-inflammatory effects of kappa-opioid ligands in laboratory animals with induced neuroinflammation.Materials and methods. The databases, such as Google Scholar, PubMed, ScienceDirect, Scopus, e-Library were used as search tools. The search comprised the following keywords and phrases in Russian and English: kappa opioids + neuroinflammation; kappa opioid receptors + neuroinflammation; neuroinflammation models; neuroinflammation models in rats, neuroinflammation models in mice. 148 relevant articles were found, 122 were included in this review.Results. Various experimental models of neuroinflammation, including chemically-induced and bacterial endotoxin-induced neuroinflammation, as well as traumatic and genetic models in mice and rats were evaluated. In addition, the strengths and limitations of each model were critically assessed to identify the most appropriate and reliable approach for investigating the relationship between neuroinflammation and signaling pathways associated with kappa-opioid receptors.Conclusion. The neurotropic anti-inflammatory activity of kappa-opioid ligands have been comprehensively described. The review discusses both experimental models where the effects of kappa-opioid agonists have been investigated, as well as the models where the anti-inflammatory properties of kappa-opioid agonists have not been studied yet.

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“…31 Microglia are the governors of neuronal function and homeostasis, 32 responsible for phagocytosing Aβ under normal physiological conditions. 33 However, abnormally activated microglia induce neurotoxicity and synapse loss by triggering multiple pro-inflammatory cascades, 34 and inflammatory cytokines produced during this process, in turn, compromise the phagocytosis of microglia. In the present study, HF improved oxidative damage and Aβ 1-42 deposition and suppressed abnormal microglial activation.…”

Section: Papermentioning

confidence: 99%

Hawthorn flavonoid ameliorates cognitive deficit in mice with Alzheimer's disease by increasing the levels of Bifidobacteriales in gut microbiota and docosapentaenoic acid in serum metabolites

et al. 2022

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Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses

Cited by 11 publications

References 43 publications

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

Models of neuroinflammation for the assessment of kappa-opioid receptor ligands

Hawthorn flavonoid ameliorates cognitive deficit in mice with Alzheimer's disease by increasing the levels of Bifidobacteriales in gut microbiota and docosapentaenoic acid in serum metabolites

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