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      Exogenous neuregulin-1 attenuates STZ-induced diabetic peripheral neuropathic pain in rats

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          Abstract

          Abstract Purpose: To investigate whether modulating NRG1 could attenuate diabetic neuropathic pain and analyze the underlying mechanism. Methods: Male SD rats were randomly divided into control group, diabetic group, NRG1 intervention group. After STZ-induced 2 weeks, NRG1 intervention daily for consecutive 7 days. 4 weeks after NRG1 intervention, both the mechanical withdrawal threshold and the morphological changes of the dorsal root ganglion and sural nerve were observed. Meanwhile, the expression of NGF, IL-1β, TNF-α in spinal cord were determined. Results: Compared with the diabetic group, NRG1 treatment improved the mechanical withdrawal threshold in diabetic rats, pathological changes of dorsal root ganglion and sural nerve were alleviated by NRG1 treatment with electron microscopy imagine. Moreover, compared with the control group, the expression of NGF was significantly decreased and the production of IL-1β, TNF-α were markedly induced in diabetic group. Furthermore, NRG1 treatment could normalized the above effect as compared to diabetic group. Conclusion: NRG1 exerted positive effects on the behavioral and pathological changes of rats with STZ-induced diabetic neuropathic pain, the underlying mechanism might be related to the promotion of NGF excretion and the inhibition of inflammatory cytokines excretion.

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          Most cited references 28

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          Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.

          Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1beta, IL-6, and TNFalpha on excitatory and inhibitory synaptic transmission. Whereas TNFalpha enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1beta both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFalpha and IL-1beta enhanced AMPA- or NMDA-induced currents, and IL-1beta and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress central sensitization and alleviate chronic pain.
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            Role of interleukin-1beta during pain and inflammation.

            The cytokine cascade in pain and inflammatory processes is a tremendously complex system, involving glial, immune, and neuronal cell interactions. IL-1beta is a pro-inflammatory cytokine that has been implicated in pain, inflammation and autoimmune conditions. This review will focus on studies that shed light on the critical role of IL-1beta in various pain states, including the role of the intracellular complex, the inflammasome, which regulates IL-1beta production. Evidence will be presented demonstrating the importance of IL-1beta in both the induction of pain and in the maintenance of pain in chronic states, such as after nerve injury. Additionally, the involvement of IL-1beta as a key mediator in the interaction between glia and neurons in pain states will be discussed. Taken together, the evidence presented in the current review showing the importance of IL-1beta in animal and human pain states, suggests that blockade of IL-1beta be considered as a therapeutic opportunity.
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              Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy.

              Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include painful neuropathic symptoms and insensitivity, which increases the risk for burns, injuries and foot ulceration. Several recent studies have implicated poor glycaemic control, duration of diabetes, hyperlipidaemia (particularly hypertryglyceridaemia), elevated albumin excretion rates and obesity as risk factors for the development of DPN. Although there is now strong evidence for the importance of nerve microvascular disease in the pathogenesis of DPN, the risk factors for painful DPN are not known. However, emerging evidence regarding the central correlates of painful DPN is now afforded by brain imaging. The diagnosis of DPN begins with a careful history of sensory and motor symptoms. The quality and severity of neuropathic pain if present should be assessed using a suitable scale. Clinical examination should include inspection of the feet and evaluation of reflexes and sensory responses to vibration, light touch, pinprick and the 10-g monofilament. Glycaemic control and addressing cardiovascular risk is now considered important in the overall management of the neuropathic patient. Pharmacological treatment of painful DPN includes tricyclic compounds, serotonin-norepinephrine reuptake inhibitors (e.g. duloxetine), anticonvulsants (e.g. pregabalin), opiates, membrane stabilizers, the antioxidant alpha lipoic acid and others. Over the past 7 years, new agents with perhaps less side effect profiles have immerged. Management of patients with painful neuropathy must be tailored to individual requirements and will depend on the presence of other co-morbidities. There is limited literature with regard to combination treatment. Copyright © 2012 John Wiley & Sons, Ltd.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                acb
                Acta Cirurgica Brasileira
                Acta Cir. Bras.
                Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia (São Paulo, SP, Brazil )
                0102-8650
                1678-2674
                January 2017
                : 32
                : 1
                : 28-37
                S0102-86502017000100028
                10.1590/s0102-865020170104

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                Figures: 0, Tables: 0, Equations: 0, References: 29, Pages: 10
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                Product Information: SciELO Brazil

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