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      Interleukin-10 Reduces Neurogenic Inflammation and Pain Behavior in a Mouse Model of Type 2 Diabetes

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          Abstract

          Purpose

          Neurogenic inflammation is a major component of chronic neuropathic pain. Previously, we established the db/db mouse as an animal model of painful diabetic neuropathy (PDN) of type 2 diabetes. In the current study, we investigate the roles of interleukin (IL)-10, an anti-inflammatory cytokine, in the development of neurogenic inflammation and pain behavior in db/db mouse.

          Materials and Methods

          We first studied IL-10 expression in lumbar dorsal root ganglion (LDRG) neurons of db/db mice using immunohistochemistry, immunoblots, and reverse transcription polymerase chain reaction during the period of pain behavior (from 8 to 16 wk of age). To determine if the reduced IL-10 expression mediates the mechanical allodynia in db/db mice, we administered recombinant mouse IL-10 or saline (control) intraperitoneally to control db/+ and db/db mice starting at 8 wk of age. IL-10 treatment was repeated every other day for 2 wk until the mice reached 10 wk of age.

          Results

          During the period of pain behavior, reduction of IL-10 protein and gene expression was detected in LDRG of db/db mice. Treatment with recombinant IL-10, from 8 to 10 wk of age, alleviates pain behaviors in db/db mice without affecting other diabetic parameters. In parallel, IL-10 treatment reduced the upregulation of nerve growth factor (NGF), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and high-affinity NGF receptor (Trk A) in LDRG, as well as the numbers of iNOS-positive Langerhans cells and CD-68-positive dermal dendritic cells in the hind-foot-pad skin in db/db mice.

          Conclusion

          Our findings suggest that the reduction in neuronal IL-10 increases inflammatory phenomena, ultimately contributing to PDN. These results suggest that the dysregulation of cytokine-mediated inflammation contributes to the development of PDN in db/db mice. Targeting this pathophysiologic mechanism could be an effective approach for treating PDN in type 2 diabetes.

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          Most cited references 58

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          Diabetic Neuropathies: A statement by the American Diabetes Association

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            Quantitative assessment of tactile allodynia in the rat paw

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              Diabetic neuropathy: mechanisms to management.

              Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                29 December 2020
                2020
                : 13
                : 3499-3512
                Affiliations
                [1 ]Department of Neurology, University of Michigan Medical Center , Ann Arbor, Michigan, USA
                [2 ]Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts, USA
                Author notes
                Correspondence: Hsinlin T Cheng Massachusetts General Hospital, Harvard Medical School , WACC 835, 55 Fruit Street, Boston, MA02114, USATel +1 2 617-724-6213Fax +1 2 617-724-0895 Email htcheng@mgh.harvard.edu
                Article
                264136
                10.2147/JPR.S264136
                7778525
                © 2020 Yanik et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, References: 58, Pages: 14
                Categories
                Original Research

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