Microglia Express Mu Opioid Receptor: Insights From Transcriptomics and Fluorescent Reporter Mice

Maduna, Tando; Audouard, Emilie; Dembelé, Doulaye; Mouzaoui, Nejma; Reiss, David J; Massotte, Dominique; Gavériaux‐Ruff, Claire

doi:10.3389/fpsyt.2018.00726

Cited by 58 publications

(40 citation statements)

References 101 publications

(146 reference statements)

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“…Using immunofluorescence in transgenic mice expressing MOP receptors in microglia (CX3CR1-eGFP-MOP-mCherry), the percentage of MOP receptor-positive microglial cells ranged between 35 and 52% in brain, and between 37 and 42% in the spinal cord. The presence of MOP receptor protein in Golgi apparatus suggested that the receptors might be synthetized by microglia (100). Utilizing MOP-mCherry mice and double labeling in wild-type mice using astrocyte marker and MOP receptor antibodies (whose staining specificity was confirmed in MOP receptor knockout mice), MOP receptor protein was detected in astrocytes in various brain regions (107).…”

Section: Gliamentioning

confidence: 99%

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

2020

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neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca 2+ -regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.

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Section: Gliamentioning

confidence: 99%

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

2020

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“…As mentioned in the section above, several drugs of abuse, but particularly opioids, have been shown to directly activate microglia through TLR4 and/or mu (μ) opioid receptors on resident microglia [ 199 , 325 ], whereby μ opioid receptor activation accentuates lipopolysaccharide (LPS)-induced microglia activation-mediated NF-kB signaling [ 103 , 141 ]. Importantly, LPS is both a microbial product and can be exogenously infused to induce sepsis, and subsequently, an immune response.…”

Section: Developing An Understanding Of the Interactions Between Neurmentioning

confidence: 99%

Interactions of neuroimmune signaling and glutamate plasticity in addiction

Gipson

Rawls

Scofield

et al. 2021

J Neuroinflammation

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Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.

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“…Drugs reported to selectively attenuate glial inflammation block morphine conditioned place preference and attenuate symptoms of opioid withdrawal (Narita et al 2006 ; Hutchinson et al 2009 ; Liu et al 2010 ). μ (MOR), δ (DOR), and κ (KOR) opioid receptors are expressed by subsets of astrocytes and microglia (Stiene-Martin and Hauser 1991 ; Eriksson et al 1992 ; Stiene-Martin et al 1993 ; Ruzicka et al 1995 ; Gurwell et al 1993 ; Hauser et al 1996 ; Turchan-Cholewo et al 2008 ; Maduna et al 2018 ) and are involved in opioid tolerance and dependence to varying degrees (Kieffer and Gaveriaux-Ruff 2002 ; Berger and Whistler 2010 ; Morgan and Christie 2011 ). Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al 2008 ; Hutchinson et al 2010 ; Coller and Hutchinson 2012 ; Hutchinson et al 2012 ; Theberge et al 2013 ; Lacagnina et al 2017 ) by binding to a myeloid differentiation protein-2 intermediary (Wang et al 2012 ), this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019 ).…”

Section: Overviewmentioning

confidence: 99%

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Fitting

McRae

Hauser

2020

J Neuroimmune Pharmacol

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With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

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Microglia Express Mu Opioid Receptor: Insights From Transcriptomics and Fluorescent Reporter Mice

Cited by 58 publications

References 101 publications

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

Interactions of neuroimmune signaling and glutamate plasticity in addiction

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

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