Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain

Cuitavi, Javier; Torres-Pérez, Jose Vicente; Lorente, Jesús David; Andrés-Herrera, Paula; Polache, Ana; Agustín-Pavón, Carmen; Hipólito, Lucía

doi:10.1016/j.neubiorev.2022.105011

Cited by 26 publications

(13 citation statements)

References 152 publications

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“…Furthermore, in a striking parallel to the sex differences we saw in the regulation of oligodendroglial activity, female rats showed the same broad directionality as males, except that greater neuroimmune activities were found in resilient animals. This suggests that proinflammatory responses to opioids (Butelman et al, 2023; Eidson & Murphy, 2019; Seney et al, 2021) may in fact serve a protective function in the domain of opioid addiction liability at the same time that anti-inflammatory responses tend to promote the analgesic effects of opioids (Cuitavi et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder

Liu,

Muelken,

Maxim

et al. 2024

Preprint

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Opioid use disorder (OUD) is a neuropsychological disease that causes immense distress to individuals and the society. Despite the abundant clinical and preclinical studies demonstrating substantial individual differences in OUD vulnerability, the neurobiological mechanisms underlying such individual variability in OUD vulnerability remain unclear, hindering the progress in the development of more effective therapeutics. To address this question, we investigated the transcriptome (RNA-seq) and genome-wide chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats given morphine and exhibiting differential vulnerability to OUD as measured in behavioral paradigms capturing different phases of the disorder: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD. Weighted Gene Co-Expression Network Analysis and IPA analyses suggested an involvement of myelination and oligodendrocyte processes, and neuroinflammation responses in the vulnerability associated with WIA and Demand paradigm, respectively. HOMER motif analysis of ATAC-seq showed changes in accessibility to a small set of transcription factor (TF) binding sites, some that were shared across the 3 paradigms and others that were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and disease vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder.

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Section: Discussionmentioning

confidence: 99%

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder

Liu,

Muelken,

Maxim

et al. 2024

Preprint

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“…Whether MOR activation triggers neuroinflammatory processes is unclear, although some researchers suggest that this might be the case (Cuitavi et al, 2022; Gessi et al, 2016; Merighi et al, 2013; Shrivastava et al, 2017). However, to the best of our knowledge, this has mainly been tested in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the presence of inflammatory pain significantly increased microglial activation in the DAMGO 7 ng-treated animals when compared to pain-free animals with the same treatment. Whether MOR activation triggers neuroinflammatory processes is unclear, although some researchers suggest that this might be the case (Cuitavi et al, 2022;Gessi et al, 2016;Merighi et al, 2013;Shrivastava et al, 2017). However, to the best of our knowledge, this has mainly been tested in vitro.…”

Section: Ventral Striatal Iba1 Expression Is Altered After the Pharma...mentioning

confidence: 99%

“…In fact, they also seem to be the key to unravel MCLS‐based pain comorbidities (Campos‐Jurado et al, 2019, 2022). Furthermore, there is growing evidence that MORs play a role in the regulation of immune mechanisms (Cuitavi et al, 2022; Zhang et al, 2020). Interestingly, microglial cells express MORs in the brain and the spinal cord (Coffey et al, 2022; Leduc‐Pessah et al, 2017; Maduna et al, 2019), which might explain MORs control over inflammation under pain conditions (Machelska & Celik, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Focal mu‐opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain

Cuitavi

Andrés-Herrera

Meseguer

et al. 2023

Glia

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Microglia participates in the modulation of pain signaling. The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu-opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1α, IL1β, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1-positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose-dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO-induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia-MOR relationship could be pivotal to unravel some inflammatory pain-induced comorbidities related to MCLS dysfunction.

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“…Neuroinflammation and oxidative stress contribute to a variety of neuropathological diseases and mental health disorders, such as chronic neurodegeneration [ 1 ] and drug addiction [ 2 ]. Microglia are resident immune cells in the central nervous system (CNS) and play a key role in neuroinflammatory and immune responses [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

A natural small molecule aspidosperma-type alkaloid, hecubine, as a new TREM2 activator for alleviating lipopolysaccharide-induced neuroinflammation in vitro and in vivo

Li,

He,

et al. 2024

Redox Biology

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Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain

Cited by 26 publications

References 152 publications

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder

Focal mu‐opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain

A natural small molecule aspidosperma-type alkaloid, hecubine, as a new TREM2 activator for alleviating lipopolysaccharide-induced neuroinflammation in vitro and in vivo

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