title: Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston2Department of Neurobiology, Harvard Medical School, Boston, Massachusetts3Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts4Department of Cardiology, Boston Ch.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston2Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Arjun
authors.initials: A
authors.lastname: Khanna
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts4Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts5Manton Center for Orphan Disease Research, Boston, Massachusetts.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts7Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D018118:Chloride Channels / Q000502:physiology; D006801:Humans; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D027981:Symporters / Q000819:agonists / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D000700:Analgesics; D018118:Chloride Channels; D027981:Symporters; D000096922:K Cl- Cotransporters