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From: Therapeutic Restoration of Spinal Inhibition via Druggable Enhancement of Potassium-Chloride Cotransporter KCC2–Mediated Chloride Extrusion in Peripheral Neuropathic Pain JAMA Neurol. 2014;71(5):640-645. doi:10.1001/jamaneurol.2014.21 Figure Legend: Dysfunction of γ-Aminobutyric Acid (GABA)–ergic Signaling in the Superficial Dorsal Horn in Neuropathic PainIn normal function, nociceptive fibers innervate peripheral tissues and form excitatory (glutamatergic) synapses onto secondary sensory neurons in superficial laminae (I and II) of the dorsal horn. Within the dorsal horn, GABAergic interneurons organized in polysynaptic translaminar networks regulate nociceptive signals by inhibiting primary and secondary neurons. Activity of KCC2 in sensory −) concentration. Consequently, GABA type A receptor (GABA R) activation by neurons maintains a low intracellular chloride (ClCopyright A © 2014 American Medical − Date of download: 5/14/2017 GABA released from interneurons results in Cl influx and neuronal hyperpolarization. Neuropathic pain is characterized by Association. All rights reserved. dysregulation of inhibitory networks. Some inhibitory interneurons undergo apoptosis, and GABA synthesis and release by From: Therapeutic Restoration of Spinal Inhibition via Druggable Enhancement of Potassium-Chloride Cotransporter KCC2–Mediated Chloride Extrusion in Peripheral Neuropathic Pain JAMA Neurol. 2014;71(5):640-645. doi:10.1001/jamaneurol.2014.21 Figure Legend: Potassium-Chloride Cotransporter KCC2 as a Slider Control of Neuronal Excitabilityγ-Aminobutyric acid (GABA) type A receptors (GABAARs) are ligand-gated chloride (Cl−) channels whose effect on membrane potential (Vm) depends on intracellular Cl− concentration ([Cl−]i). When GABAAR channels are opened, the Vm is pulled toward the Cl− equilibrium potential (ECl), which is determined by [Cl−]i and the extracellular Cl− concentration ([Cl−]e), the latter of which remains relatively constant. The potassium [K+]–Cl− cotransporter KCC2 is the major Cl− efflux mechanism neurons.Medical Thus, activity of KCC2 is a major determinant of [Cl −]i Copyright © 2014ofAmerican Date of download: 5/14/2017 and, consequently, the effect of GABAAR activation on Vm. In conditions of low KCC2 activity, such as early in development or in Association. All rights reserved. – + certain neuropathic pain states, Cl influx mechanisms (eg, sodium-K –Cl– cotransporter 1 [NKCC1], not shown) outweigh KCC2- From: Therapeutic Restoration of Spinal Inhibition via Druggable Enhancement of Potassium-Chloride Cotransporter KCC2–Mediated Chloride Extrusion in Peripheral Neuropathic Pain JAMA Neurol. 2014;71(5):640-645. doi:10.1001/jamaneurol.2014.21 Figure Legend: Potassium-Chloride Cotransporter KCC2 Activation as a Potential Therapeutic Strategy for Neuropathic PainFunctional downregulation of KCC2 activity is a major mechanism of spinal disinhibition and the development of neuropathic pain. The potassium [K+]–chloride (Cl−) cotransporter KCC2 uses the favorable outwardly directed electrochemical gradient of K + across the plasma membrane to extrude Cl− from neurons. Low intraneuronal Cl– drives Cl– influx and membrane hyperpolarization when γaminobutyric acid (GABA) binds to Cl−-permeable GABA type A receptors (GABAARs). In several pathogenic pain states (and in Copyright © 2014 American Medical Date download: 5/14/2017 otherofneurological diseases such as epilepsy and Association. spasticity), the functional expression of KCC2 activity is decreased and the All rights reserved. − − intracellular Cl concentration ([Cl ] ) increases. As a result, GABA R activation fails to hyperpolarize cells and instead can