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      Microbes, microglia, and pain

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          Highlights

          • Explore the connection between the gut microbiome and microglia in chronic pain.

          • Discuss mechanisms by which gut bacteria might influence microglia to contribute to chronic pain.

          • Highlight gaps in knowledge and discuss future directions for the field.

          Abstract

          Globally, it is estimated that one in five people suffer from chronic pain, with prevalence increasing with age. The pathophysiology of chronic pain encompasses complex sensory, immune, and inflammatory interactions within both the central and peripheral nervous systems. Microglia, the resident macrophages of the central nervous system (CNS), are critically involved in the initiation and persistence of chronic pain. Microglia respond to local signals from the CNS but are also modulated by signals from the gastrointestinal tract. Emerging data from preclinical and clinical studies suggest that communication between the gut microbiome, the community of bacteria residing within the gut, and microglia is involved in producing chronic pain. Targeted strategies that manipulate or restore the gut microbiome have been shown to reduce microglial activation and alleviate symptoms associated with inflammation. These data indicate that manipulations of the gut microbiome in chronic pain patients might be a viable strategy in improving pain outcomes. Herein, we discuss the evidence for a connection between microglia and the gut microbiome and explore the mechanisms by which commensal bacteria might influence microglial reactivity to drive chronic pain.

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          Most cited references79

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          Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

          Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.
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            Different immune cells mediate mechanical pain hypersensitivity in male and female mice.

            A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.
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              MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4

              Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.
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                Author and article information

                Contributors
                Journal
                Neurobiol Pain
                Neurobiol Pain
                Neurobiology of Pain
                Elsevier
                2452-073X
                29 January 2020
                Jan-Jul 2020
                29 January 2020
                : 7
                : 100045
                Affiliations
                [a ]Department of Pharmacology, University of Alberta, Edmonton T6G2H7, Canada
                [b ]Neuroscience and Mental Health Institute, University of Alberta, Edmonton T6G2H7, Canada
                [c ]Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton T6G2H7, Canada
                Author notes
                [* ]Corresponding author at: Department of Pharmacology, University of Alberta, 8613 114 Street N.W., MSB 9-47, Edmonton, Alberta, Canada. Ataylor1@ 123456ualberta.ca
                Article
                S2452-073X(20)30003-9 100045
                10.1016/j.ynpai.2020.100045
                7016021
                32072077
                14bca742-b6f6-4865-a2e5-7cce63831a02
                © 2020 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 8 January 2020
                : 23 January 2020
                : 24 January 2020
                Categories
                Article(s) from the Special Issue on on Microbiome and Pain; Edited by Dr. Siobhain O'Mahony and Dr. Anna Taylor

                microglia,gut microbiome,vagus nerve,gut permeability,chronic pain,gut-brain axis

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