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      Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

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          Abstract

          In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.

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          Most cited references177

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          Neuronal plasticity: increasing the gain in pain.

          We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
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            Different immune cells mediate mechanical pain hypersensitivity in male and female mice.

            A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.
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              P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.

              Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                September 2016
                13 September 2016
                1 September 2016
                : 6
                : 9
                : e888
                Affiliations
                [1 ]Discipline of Physiology, School of Medicine, University of Adelaide , Adelaide, SA, Australia
                [2 ]Discipline of Pharmacology, School of Medicine, University of Adelaide , Adelaide, SA, Australia
                [3 ]Pelvic Pain SA , Norwood, SA, Australia
                [4 ]Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder , Boulder, CO, USA
                [5 ]ARC Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide , Adelaide, SA, Australia
                Author notes
                [* ]Discipline of Physiology, School of Medicine, University of Adelaide , Medical School North 416, Frome Road, Adelaide, SA 5005, Australia. E-mail: kelsi.dodds@ 123456adelaide.edu.au
                Article
                tp2016168
                10.1038/tp.2016.168
                5048206
                27622932
                debd9a69-2cb7-40fe-8019-c8471bb01204
                Copyright © 2016 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 02 June 2016
                : 14 July 2016
                : 22 July 2016
                Categories
                Review

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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