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      The role of miR-190a-5p contributes to diabetic neuropathic pain via targeting SLC17A6

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          Abstract

          Introduction

          MicroRNAs play a key role in neuropathic pain. In a previous study, miR-190a-5p was significantly downregulated in diabetic neuropathic pain (DNP). However, the role and pathological mechanism of miR-190a-5p in DNP still remain unclear.

          Materials and methods

          DNP model was established. The paw withdrawal thresholds were measured to assess the mechanical nociceptive response. Dual-luciferase reporter assay was used to confirm the target gene of microRNA. The expressions of microRNA, gene, and protein were detected by the quantitative real-time polymerase chain reaction or Western blot. The levels of IL-1β and IL-6 were detected with the enzyme-linked immuno sorbent assay.

          Results

          Compared with the control sample, the expression of miR-190a-5p was decreased and SLC17A6 was increased in the spinal tissue from those developing DNP. The bioinformatics and luciferase reporter assay demonstrated that SLC17A6 is a direct target of miR-190a-5p. Up-regulation of miR-190a-5p and inhibition of SLC17A6 could significantly weaken the painful behavior and reduce IL-1β and IL-6 level in DNP.

          Conclusion

          miR-190a-5p is involved in DNP via targeting SLC17A6, and miR-190a-5p and SLC17A6 may be the therapeutic targets of this disease.

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          Most cited references 29

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          New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.

          Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.
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            Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

            Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
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              Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats.

              Diabetes mellitus is the leading cause of peripheral neuropathy worldwide. Despite this high level of incidence, underlying mechanisms of the development and maintenance of neuropathic pain are still poorly understood. Evidence supports a prominent role of glial cells in neuropathic pain states. Gabapentin is used clinically and shows some efficacy in the treatment of neuropathic pain. Here we investigate the distribution and activation of spinal microglia and astrocytes in streptozotocin (STZ)-diabetic rats and the effect of the gold standard analgesic, Gabapentin, on these cells. Mechanical allodynia was observed in four week-diabetic rats. Oral administration of Gabapentin significantly attenuated mechanical allodynia. Quantification of cell markers Iba-1 for microglia and GFAP for astrocytes revealed extensive activation of microglia in the dorsal horn of diabetic rats, whereas a reduction in the number of astrocytes could be observed. In addition, an attenuation of microglial activation correlated with reduced allodynia following Gabapentin treatment, while Gabapentin had no effect on the number of astrocytes. Here we show a role of microglia in STZ-induced mechanical allodynia and furthermore, that the anti-allodynic effect of Gabapentin may be linked to a reduction of spinal microglial activation. Astrocytic activation in this model appears to be limited and is unaffected by Gabapentin treatment. Consequently, spinal microglial activation is a key mechanism underlying diabetic neuropathy. Furthermore, we suggest that Gabapentin may exert its anti-allodynic actions partially through alterations of microglial cell function.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2017
                04 October 2017
                : 10
                : 2395-2403
                Affiliations
                Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
                Author notes
                Correspondence: Yao Luo, Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, No. 32 West Second Section First Ring Road, Chengdu, Sichuan 610072, China, Tel +86 182 8453 8286, Fax +86 028 8739 3875, Email yaoluo2002@ 123456sina.com
                [*]

                These authors contributed equally to this work

                Article
                jpr-10-2395
                10.2147/JPR.S133755
                5634391
                © 2017 Yang 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.

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                Original Research

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