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

Kahle, Kristopher T.; Khanna, Arjun; Clapham, David E.; Woolf, Clifford J.

doi:10.1001/jamaneurol.2014.21

Cited by 60 publications

(58 citation statements)

References 24 publications

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“…Numerous articles have reviewed ongoing efforts and prospects for therapies targeting different aspects of synaptic inhibition: restoring normal chloride regulation, [136][137][138] enhancing GABAergic transmission [139][140][141][142] or enhancing glycinergic transmission 143,144 not to mention related issues such as microglia and inflammation. Rather than repeat the details here, a few simple observations will be made to highlight the practical utility of the information conveyed earlier in this chapter.…”

Section: Implications For Therapeutic Interventionsmentioning

confidence: 99%

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Prescott

2015

Progress in Molecular Biology and Translational Science

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Section: Implications For Therapeutic Interventionsmentioning

confidence: 99%

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Prescott

2015

Progress in Molecular Biology and Translational Science

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“…In rats with ablation glycinergic neurons, 70% of IPSCs originated from purely GABAergic neurons was blocked by the glycine receptor antagonist strychnine. The data proved an important role for glycine in inhibitory input to dorsal horn neurons (58). Furthermore, activation of spinal glycinergic neurons effectively alleviates neuropathic pain (60).…”

Section: Disinhibition Of Spinal Glycine Neuronal Circuit and Allodyniamentioning

confidence: 77%

“…As KCC2 mediates Cl − extrusion, the down-regulation of KCC2 increases intracellular Cl − , following by activation of cation channels and excitation of neurons (57). In addition, enhancement of KCC2 restores spinal inhibition and reserves neuropathic pain (58). KCC2 knockdown impairs glycinergic synapse maturation in cultured spinal cord neurons (59).…”

Section: Volume 3 May 2016mentioning

confidence: 99%

“…Restoring the inhibitory tone is a reasonable therapeutic approach for neuropathic pain. The way to restore the inhibitory tone includes activation of spinal GABA receptors, inhibition of glycine transporter 2 and enhancement of chloride extrusion (58,(71)(72)(73). Nonselective GABAA receptors agonist, diazepam (DZP), binds GABAA receptors and causes the opening of Cl -channel, leading to hyperpolarization and enhancing synaptic inhibition (72).…”

Section: Treatment Of Disinhibition Of Inhibitory Interneurons In Neumentioning

confidence: 99%

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The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

Fu¹,

Wang²

2016

J Anesth Perioper Med

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Aim of review:Inhibitory interneurons, including GABAergic neurons and glycine neurons, regulate nociceptive information and non-nociceptive information in spinal dorsal horn. Emerging evidence showed that disinhibition of inhibitory interneurons of neuronal circuit in spinal dorsal horn is a pivotal mechanism of neuropathic pain after nerve injury. Method: In this view, we summarized the recent researches of the structure of inhibitory neurons in spinal dorsal horn and disinhibition of inhibitory interneurons after nerve injury and discussed the primary mechanism. Recent findings: Much progress has been made with the construction of inhibitory neuronal network in spinal dorsal horn and the dysfunction of inhibitory interneurons in these networks since inhibitory interneurons in spinal dorsal horn firstly integrate nociceptive information and non-nociceptive information from primary afferent fiber and separate non-nociceptive stimuli from nociceptive information. Disinhibitory of inhibitory interneurons underlies hyperalgesia and allodynia after nerve injury. Summary: Loss of inhibitory function of neurons in inhibitory network in the dorsal horn contributes to hyperalgesia and allodynia. The findings of these inhibitory networks provide a new evidence for preventing and curing neuropathic pain.ABSTRACT N europathic pain is a challenge for clinicians because the treatment of neuropathic pain is still unsatisfactory. Therefore, increasing understanding of the mechanisms that underlie neuropathic pain will be beneficial for the discovery of new molecular therapy targets. The gate control theory of pain is one of important mechanisms of pain. The theory is the idea that physical pain is modulated by interaction between different neurons. According to the postulate of Melzack and Wall (1), the nerve fibers project to the substantia gelatinosa (SG) of the dorsal horn and the first central transmission cells of the spinal cord. Inhibitory interneurons in the SG act as the gate and determine which signals should reach the T cells and then go further through the spinothalamic tract to reach the brain. Thus, spinal inhibitory interneurons play an important role in maintaining normal pain. Spinal dorsal horn is the first site of integration of nociceptive and nonnociceptive information within the central nervous system (CNS). Under normal physiological conditions, spinal inhibitory interneurons, including gammaaminobutyric acid (GABA) neurons and glycine neurons, form axo-axonic contacts with the termination of primary afferent fiber (PAF), exerting presynaptic inhibition control over sensory transmission. Meanwhile, these inhibitory interneurons generate postsynaptic inhibi-

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“…KCC2 controls neuron-specific localization throughout the CNS, including hippocampus, cerebral cortex, brainstem, cerebellum, and spinal cord [19][20][21]. The messenger RNA (mRNA) levels of KCC2 in the cerebral cortex and hippocampus dramatically increase around postnatal day 15 (P15) and exhibit a basic expression pattern thereafter [22].…”

Section: Kcc2: Structure Expression and Functionmentioning

confidence: 99%

The K+–Cl− Cotransporter KCC2 and Chloride Homeostasis: Potential Therapeutic Target in Acute Central Nervous System Injury

Che

Tang

et al. 2015

Mol Neurobiol

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The K(+)-Cl(-) cotransporter-2 (KCC2) is a well-known member of the electroneutral cation-chloride cotransporters with a restricted expression pattern to neurons. This transmembrane protein mediates the efflux of Cl(-) out of neurons and exerts a critical role in inhibitory γ-aminobutyric acidergic (GABAergic) and glycinergic neurotransmission. Moreover, KCC2 participates in the regulation of various physiological processes of neurons, including cell migration, dendritic outgrowth, spine morphology, and dendritic synaptogenesis. It is important to note that down-regulation of KCC2 is associated with the pathogenesis of multiple neurological diseases, which is of particular relevance to acute central nervous system (CNS) injury. In this review, we aim to survey the pathogenic significance of KCC2 down-regulation under the condition of acute CNS injuries. We propose that further elucidation of the molecular mechanisms regarding KCC2 down-regulation after acute CNS injuries is necessary because of potential promising avenues for prevention and treatment of acute CNS injury.

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

Cited by 60 publications

References 24 publications

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

The K+–Cl− Cotransporter KCC2 and Chloride Homeostasis: Potential Therapeutic Target in Acute Central Nervous System Injury

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