Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity

Tang, Dongfang; Qian, Aihua; Song, Dandan; Ben, Qiwen; Yao, Weiyan; Sun, Jing; Li, Wei‐Guang; Xu, Tian‐Le; Yuan, Yaozong

doi:10.1152/ajpgi.00313.2014

Cited by 19 publications

(20 citation statements)

References 44 publications

(60 reference statements)

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“…Impaired KCC2 activity causes Cl − accumulation, weakening the strength of GABA A /glycine receptor-mediated inhibition 12–14 . Disinhibition in the SDH due to decreased KCC2 function translates behaviorally into an increased pain sensitivity, that has been consistently reported in a number of different pain models 9, 13, 15–20 .…”

Section: Introductionmentioning

confidence: 72%

Enhancing KCC2 function counteracts morphine-induced hyperalgesia

Ferrini

Lorenzo

Godin

et al. 2017

Sci Rep

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Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl− extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABAA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6–8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in E GABA under Cl− load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl− extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH.

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Section: Introductionmentioning

confidence: 72%

Enhancing KCC2 function counteracts morphine-induced hyperalgesia

Ferrini

Lorenzo

Godin

et al. 2017

Sci Rep

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“…The involvement of KCC2-mediated impairment of spinal (Cl − ) homeostasis has been reported in rats with chronic water avoidance stress (WAS)-induced visceral hyperalgesia [36]. Similarly, in a nerve injury model, intrathecal delivery of KCC2 using lentiviral vector results in a complete and long-lasting reversal of pain hypersensitivity by restoring Cl − homeostasis both at spinal and peripheral levels [14].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

Zhang

Kannampalli

et al. 2017

Pain

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Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b–mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan–treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b-3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p–mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis.

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“…The flux was multiplied by the surface area between compartments and then divided by compartment 835 volume to determine the flux in terms of molar concentration (M/s), i.e. Tang et al, 2015). However, one study did not report the change in Vm and hence was excluded from 854 the figure (Mahadevan et al, 2015).…”

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confidence: 99%

Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Düsterwald

Currin

Burman

et al. 2017

Preprint

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Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl− ions based on the neuronal Cl− driving force. Established theories regarding the determinants of Cl− driving force have recently been questioned. Here we present biophysical models of Cl− homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl− driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl−]i in neurons, they have a negligible effect on the driving force for Cl− locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl− driving force and hence inhibitory signalling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

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Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity

Cited by 19 publications

References 44 publications

Enhancing KCC2 function counteracts morphine-induced hyperalgesia

Enhancing KCC2 function counteracts morphine-induced hyperalgesia

MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

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