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      Novel targets for Spinal Cord Injury related neuropathic pain

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          Abstract

          Millions of people suffer from spinal cord injury (SCI) with little known effective clinical therapy. Neuropathic pain (NP) is often accompanied with SCI, making clinical treatment challenging. Even though the key mediators in the development of NP have been discovered, the pathogenesis is still unclear. Some of the key mediators in the sustenance of NP include the inflammatory processes, cannabinoid receptors, matrix metalloproteases, and their tissue inhibitors. Animal models have shown promising results with modulation of these mediators, yet the clinical models have been unsuccessful. One such study with matrix metalloproteases (MMPs) has yielded encouraging results. The relationship between MMPs and their tissue inhibitors (TIMPs) plays a significant role in the pathogenesis and recovery of SCI and the CNS. Key factors that lead to the functional consequences of MMP activity are cellular localization, tissue distribution, and temporal pattern of MMP expression. Studies concluding that MMPs can be seen as contributors of tissue damage and as contributors in the repair mechanisms have provided a need to reexamine their roles after acute and chronic neuropathic pain

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          Most cited references 75

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          Matrix metalloproteinases.

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            BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.

            Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.
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              AP-1 function and regulation.

              AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.
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                Author and article information

                Journal
                Ann Neurosci
                Ann Neurosci
                ANS
                Annals of Neurosciences
                Indian Academy of Neurosciences
                0972-7531
                0976-3260
                October 2011
                : 18
                : 4
                : 162-167
                Affiliations
                Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
                Author notes
                [* ]Corresponding Author: Department of Neurological Surgery University of Wisconsin School of Medicine and Public Health, K4/834 Clinical Science Center, 600 Highland Ave Madison, WI 53792(608) 263-9651 Resnick@ 123456neurosurg.wisc.edu
                Article
                11180413
                10.5214/ans.0972.7531.1118413
                4116958
                Copyright © 2011, Annals of Neurosciences
                Categories
                Mini Review
                Neuropathology Reviews

                timps, spinal cord injury, mmps, neuropathic pain

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