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      Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain

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      1 , , 1 , 2 , 3
      Molecular Pain
      BioMed Central

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          Abstract

          Background

          Reduction of the transmembrane chloride gradient in spinal lamina I neurons contributes to the cellular hyperexcitability producing allodynia and hyperalgesia after peripheral nerve injury. The resultant decrease in anion reversal potential ( i.e. shift in E anion to less negative potentials) reduces glycine/GABA A receptor-mediated hyperpolarization, but the large increase in membrane conductance caused by inhibitory input can nonetheless shunt concurrent excitatory input. Without knowing the relative contribution of hyperpolarization and shunting to inhibition's modulation of firing rate, it is difficult to predict how much net disinhibition results from reduction of E anion. We therefore used a biophysically accurate lamina I neuron model to investigate quantitatively how changes in E anion affect firing rate modulation.

          Results

          Simulations reveal that even a small reduction of E anion compromises inhibitory control of firing rate because reduction of E anion not only decreases glycine/GABA A receptor-mediated hyperpolarization, but can also indirectly compromise the capacity of shunting to reduce spiking. The latter effect occurs because shunting-mediated modulation of firing rate depends on a competition between two biophysical phenomena: shunting reduces depolarization, which translates into reduced spiking, but shunting also shortens the membrane time constant, which translates into faster membrane charging and increased spiking; the latter effect predominates when average depolarization is suprathreshold. Disinhibition therefore occurs as both hyperpolarization- and shunting-mediated modulation of firing rate are subverted by reduction of E anion. Small reductions may be compensated for by increased glycine/GABA A receptor-mediated input, but the system decompensates ( i.e. compensation fails) as reduction of E anion exceeds a critical value. Hyperexcitability necessarily develops once disinhibition becomes incompensable. Furthermore, compensation by increased glycine/GABA A receptor-mediated input introduces instability into the system, rendering it increasingly prone to abrupt decompensation and even paradoxical excitation.

          Conclusion

          Reduction of E anion dramatically compromises the inhibitory control of firing rate and, if compensation fails, is likely to contribute to the allodynia and hyperalgesia associated with neuropathic pain. These data help explain the relative intractability of neuropathic pain and illustrate how it is important to choose therapies not only based on disease mechanism, but based on quantitative understanding of that mechanism.

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          Most cited references98

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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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            Influence of dendritic structure on firing pattern in model neocortical neurons.

            Neocortical neurons display a wide range of dendritic morphologies, ranging from compact arborizations to highly elaborate branching patterns. In vitro electrical recordings from these neurons have revealed a correspondingly diverse range of intrinsic firing patterns, including non-adapting, adapting and bursting types. This heterogeneity of electrical responsivity has generally been attributed to variability in the types and densities of ionic channels. We show here, using compartmental models of reconstructed cortical neurons, that an entire spectrum of firing patterns can be reproduced in a set of neurons that share a common distribution of ion channels and differ only in their dendritic geometry. The essential behaviour of the model depends on partial electrical coupling of fast active conductances localized to the soma and axon and slow active currents located throughout the dendrites, and can be reproduced in a two-compartment model. The results suggest a causal relationship for the observed correlations between dendritic structure and firing properties and emphasize the importance of active dendritic conductances in neuronal function.
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              Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.

              Modern pain-control theory predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes. However, the nature of the mechanisms that underlie such disinhibition has remained controversial. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium-chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.
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                Author and article information

                Journal
                Mol Pain
                Molecular Pain
                BioMed Central (London )
                1744-8069
                2006
                13 October 2006
                : 2
                : 32
                Affiliations
                [1 ]Computational Neurobiology Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
                [2 ]Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
                [3 ]Division de Neurobiologie Cellulaire, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec, Canada G1J 2G3
                Article
                1744-8069-2-32
                10.1186/1744-8069-2-32
                1624821
                17040565
                64a52a15-6d99-410d-ac87-0c6361f7a965
                Copyright © 2006 Prescott et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 July 2006
                : 13 October 2006
                Categories
                Research

                Molecular medicine
                Molecular medicine

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