Peripheral neuropathic pain, typified by the development of spontaneous pain or pain hypersensitivity following injury to the peripheral nervous system, is common, greatly impairs quality of life, and is inadequately treated with available drugs. Maladaptive changes in chloride homeostasis due to a decrease in the functional expression of the potassium-chloride cotransporter KCC2 in spinal cord dorsal horn neurons are a major contributor to the central disinhibition of γ-aminobutyric acid type A receptor– and glycine receptor–mediated signaling that characterizes neuropathic pain. A compelling novel analgesic strategy is to restore spinal ionotropic inhibition by enhancing KCC2-mediated chloride extrusion. We review the data on which this theory of alternative analgesia is based, discuss recent high-throughput screens that have searched for small-molecule activators of KCC2, and propose other strategies of KCC2 activation based on recent developments in the basic understanding of KCC2’s functional regulation. Exploiting the chloride-dependent functional plasticity of the γ-aminobutyric acid and glycinergic system by targeting KCC2 may be a tenable method of restoring ionotropic inhibition not only in neuropathic pain but also in other “hyperexcitable” diseases of the nervous system such as seizures and spasticity.
In 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 neurons maintains a low intracellular chloride (Cl−) concentration. Consequently, GABA type A receptor (GABAAR) activation by GABA released from interneurons results in Cl− influx and neuronal hyperpolarization. Neuropathic pain is characterized by dysregulation of inhibitory networks. Some inhibitory interneurons undergo apoptosis, and GABA synthesis and release by interneurons decrease. Furthermore, KCC2 activity is significantly reduced, resulting in the accumulation of Cl− within neurons. Thus, GABAAR activation results in reduced hyperpolarization and may even result in depolarization (excitation). Together, these effects result in disinhibition of primary afferent fibers and fewer inhibitory postsynaptic currents, leading to hyperalgesia and allodynia. CNS indicates central nervous system; Glu, glutamate; K+, potassium; and PNS, peripheral nervous system. Adapted with permission from Elsevier.4
γ-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 of neurons. Thus, activity of KCC2 is a major determinant of [Cl−]i and, consequently, the effect of GABAAR activation on Vm. In conditions of low KCC2 activity, such as early in development or in certain neuropathic pain states, Cl– influx mechanisms (eg, sodium-K+–Cl– cotransporter 1 [NKCC1], not shown) outweigh KCC2-mediated Cl– efflux, resulting in a high [Cl−]i and subsequently a more depolarized ECl. Activation of GABAARs depolarizes the cell. Increasing KCC2 activity or expression lowers [Cl−]i and hyperpolarizes ECl. In conditions of high KCC2 expression and activity, such as in healthy, mature neurons, KCC2-mediated efflux maintains low [Cl−]i and hyperpolarized ECl such that GABAAR activation results in neuronal hyperpolarization.
Functional 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 γ-aminobutyric acid (GABA) binds to Cl−-permeable GABA type A receptors (GABAARs). In several pathogenic pain states (and in other neurological diseases such as epilepsy and spasticity), the functional expression of KCC2 activity is decreased and the intracellular Cl− concentration ([Cl−]i) increases. As a result, GABAAR activation fails to hyperpolarize cells and instead can depolarize and even excite neurons. Pharmacological enhancement of KCC2 activity, which could be achieved by increasing the intrinsic activity of transporters already at the cell surface or by promoting the increased insertion or decreased retrieval of transporters to and from the cell surface, respectively, would be expected to lower neuronal Cl− levels and restore GABAergic inhibition of neurons in the nociceptive pathway. Endogenous regulators specific for KCC2 activity (eg, kinases, phosphatases, trafficking machinery, and/or degradation enzymes) are prime potential targets for therapeutic intervention. P indicates phosphorylation. Adapted with permission from Macmillan Publishers Ltd.18
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