We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Implications of Basic Neuroscience Research |

Therapeutic Restoration of Spinal Inhibition via Druggable Enhancement of Potassium-Chloride Cotransporter KCC2–Mediated Chloride Extrusion in Peripheral Neuropathic Pain

Kristopher T. Kahle, MD, PhD1,2,3,4,5; Arjun Khanna, BS1,2; David E. Clapham, MD, PhD3,4,5; Clifford J. Woolf, MD, PhD6,7
[+] Author Affiliations
1Department of Neurosurgery, Massachusetts General Hospital, Boston
2Department of Neurobiology, Harvard Medical School, Boston, Massachusetts
3Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts
4Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
5Manton Center for Orphan Disease Research, Boston, Massachusetts
6F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
7Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Neurol. 2014;71(5):640-645. doi:10.1001/jamaneurol.2014.21.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal


Place holder to copy figure label and caption
Figure 1.
Dysfunction of γ-Aminobutyric Acid (GABA)–ergic Signaling in the Superficial Dorsal Horn in Neuropathic Pain

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

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Potassium-Chloride Cotransporter KCC2 as a Slider Control of Neuronal Excitability

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.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Potassium-Chloride Cotransporter KCC2 Activation as a Potential Therapeutic Strategy for Neuropathic Pain

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

Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 2

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles