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      Journal of Pain Research (submit here)

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      Involvement of spinal glutamate transporter-1 in the development of mechanical allodynia and hyperalgesia associated with type 2 diabetes

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          Abstract

          Little is known about the effects of the development of type 2 diabetes on glutamate homeostasis in the spinal cord. Therefore, we quantified the extracellular levels of glutamate in the spinal cord of Zucker diabetic fatty (ZDF) rats using in vivo microdialysis. In addition, protein levels of glutamate transporter-1 (GLT-1) in the spinal cord of ZDF rats were measured using Western blot. Finally, the effects of repeated intrathecal injections of ceftriaxone, which was previously shown to enhance GLT-1 expression, on the development of mechanical allodynia and hyperalgesia as well as on basal extracellular level of glutamate and the expression of GLT-1 in the spinal cord of ZDF rats were evaluated. It was found that ZDF rats developed mechanical hyperalgesia and allodynia, which were associated with increased basal extracellular levels of glutamate and attenuated levels of GLT-1 expression in the spinal cord, particularly in the dorsal horn. Furthermore, repeated intrathecal administrations of ceftriaxone dose-dependently prevented the development of mechanical hyperalgesia and allodynia in ZDF rats, which were correlated with enhanced GLT-1 expression without altering the basal glutamate levels in the spinal cord of ZDF rats. Overall, the results suggested that impaired glutamate reuptake in the spinal cord may contribute to the development of neuropathic pains in type 2 diabetes.

          Most cited references36

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          Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.

          Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.
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            System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS.

            System x(c)(-) is an amino acid antiporter that typically mediates the exchange of extracellular l-cystine and intracellular L-glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of L-cystine through this transporter is critical to glutathione production and oxidative protection. The exchange-mediated export of L-glutamate takes on added significance within the CNS, as it represents a non-vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of L-cystine and the export of L-glutamate are taken into consideration, system x(c)(-) has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood-brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system x(c)(-), delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system x(c)(-) pharmacology and the structure-activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system x(c)(-) within the CNS, as it is these actions that are among the most exciting as potential long-range therapeutic targets. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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              Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy.

              This article reviews the prevalence, risk factors, natural history, and impact on quality of life of painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN). Diabetes mellitus afflicts more than 14 million persons in the U.S. An estimated 20% to 24% of these persons experience PDN. Data on risk factors for PDN are limited, but duration of diabetes mellitus and poor glycemic control are probably important factors. Painful diabetic neuropathy may interfere with general activity, mood, mobility, work, social relations, sleep, leisure activities, and enjoyment of life. Herpes zoster strikes an estimated 800,000 persons each year in the U.S., most of whom are elderly or immunosuppressed. Using pain at 3 months after rash onset as a definition of PHN, between 25% and 50% of adults older than 50 years develop PHN, depending on early antiviral therapy for herpes zoster. Increasing age, greater pain and rash severity, greater degree of sensory impairment, and psychological distress are risk factors for PHN. Postherpetic neuralgia may cause fatigue, insomnia, depression, anxiety, interference with social roles and leisure activity, and impaired basic and instrumental activities of daily living. Both conditions are common complications of their underlying disorders and can profoundly diminish the quality of life of affected persons.
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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
                2016
                28 November 2016
                : 9
                : 1121-1129
                Affiliations
                [1 ]Department of Anesthesiology, Guizhou Provincial People’s Hospital
                [2 ]Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang
                [3 ]Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin, People’s Republic of China
                Author notes
                Correspondence: Zhaoduan Li, Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin 300100, People’s Republic of China, Email lizhaoduan1984@ 123456126.com
                [*]

                These authors contributed equally to this work

                Article
                jpr-9-1121
                10.2147/JPR.S118412
                5135479
                27932896
                d93f8e3b-3a43-4ff5-8b70-4c60b390a903
                © 2016 Shi 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.

                History
                Categories
                Original Research

                Anesthesiology & Pain management
                diabetes,peripheral neuropathy,spinal cord,zucker diabetic fatty rats,glutamate,glutamate transporter-1

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