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The Role of K+-Cl-Cotransporter-2 in Neuropathic Pain

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Abstract

The pain sensory system normally functions under a fine balance between excitation and inhibition. When this balance is perturbed for some reason, it leads to neuropathic pain. There is accumulating evidence that attributes this pain generation to specific dysfunctions of the inhibitory system in the spinal cord. One possible mechanism leading to the induction of these dysfunctions is the down-regulation of K+-Cl-cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease of KCC2 expression in the spinal cord. The alteration of KCC2 expression affects GABAergic and glycinergic neurotransmissions, because KCC2 is a potassium-chloride exporter and serves to maintain intracellular chloride concentration. When there is a low level of KCC2 expression, GABAergic and glycinergic neurotransmissions transform from inhibitory signals to excitatory signals. In this review, the hypothesis that an alteration of KCC2 expression has a crucial influence on the initiation/development or maintenance of neuropathic pain is discussed. In addition, it is suggested that the alteration of inhibitory signals is dependent on the time after peripheral nerve injury.

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References

  1. Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964. doi:https://doi.org/10.1016/S0140-6736(99)01307-0

    Article  CAS  PubMed  Google Scholar 

  2. Zeilhofer HU (2005) The glycinergic control of spinal pain processing. Cell Mol Life Sci 62:2027–2035. doi:https://doi.org/10.1007/s00018-005-5107-3

    Article  CAS  PubMed  Google Scholar 

  3. Loomis CW, Khandwala H, Osmond G, Hefferan MP (2001) Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis. J Pharmacol Exp Ther 296:756–761

    CAS  PubMed  Google Scholar 

  4. Coull JAM, Boudreau D, Bachand K, Prescott SA, Nault F, De Koninck P, De Koninck Y (2003) Trans-synaptic shift in anion gradient in spinal lamina I Neurons as a mechanism of neuropathic pain. Nature 424:938–942. doi:https://doi.org/10.1038/nature01868

    Article  CAS  PubMed  Google Scholar 

  5. Mahadevan V, Woodin MA (2016) Regulation of neuronal chloride homeostasis by neuromodulaters. J Physiol 594:2593–2605. doi:https://doi.org/10.1113/JP271593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li H, Tornberg J, Kaila K, Airaksinen MS, Rivera C (2002) Patterns of cation-chloride cotransporter expression during embryonic rodent CNS development. Eur J Neurosci 16:2358–2370

    Article  PubMed  Google Scholar 

  7. Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J (2014) Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci 15:637–654. doi:https://doi.org/10.1038/nrn3819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Asiedu MN, Mejia G, Ossipov MK, Malan TP, Kaila K, Price TJ (2012) Modulation of spinal GABAergic analgesia by inhibition of chloride extrusion capacity in mice. J Pain 13:546–554. doi:https://doi.org/10.1016/j.jpain.2012.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mòdol L, Cobianchi S, Navarro X (2014) Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury. Pain 155:1577–1590. doi:https://doi.org/10.1016/j.pain.2014.05.004

    Article  PubMed  CAS  Google Scholar 

  10. Morita K, Motoyama N, Kitayama T, Morioka N, Kifune K, Dohi T (2008) Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. J Pharmacol Exp Ther 326:633–645. doi:https://doi.org/10.1124/jpet.108.136267

    Article  CAS  PubMed  Google Scholar 

  11. Kitayama T, Morita K, Motoyama N, Dohi T (2016) Down-regulation of zinc transporter-1 in astrocytes induces neuropathic pain via the brain-derived neurotrophic factor – K+-Cl co-transporter-2 signaling pathway in the mouse spinal cord. Neurochem Int 101:120–131. doi:https://doi.org/10.1016/j.neuint.2016.11.001

    Article  CAS  PubMed  Google Scholar 

  12. Okada-Ogawa A, Nakaya Y, Imamura Y, Kobayashi M, Shinoda M, Kita K, Sessle BJ, Iwata K (2015) Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection. Exp Neurol 267:42–52. doi:https://doi.org/10.1016/j.expneurol.2015.02.030

    Article  CAS  PubMed  Google Scholar 

  13. Cramer SW, Baggott C, Cain J, Tilghman J, Allcock B, Miranpuri G, Raipal S, Sun D, Resnick D (2008) The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury. Mol Pain 17:36. doi:https://doi.org/10.1186/1744-8069-4-36

    Google Scholar 

  14. Courteix C, Eschalier A, Lavarenne J (1993) Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain 53:81–88

    Article  CAS  PubMed  Google Scholar 

  15. Rerup CC (1970) Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 22:485–518.

    CAS  PubMed  Google Scholar 

  16. Schnedl WJ, Ferber S, Johnson JH, Newgard CB (1994) STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. Diabetes 43:1326–1333

    Article  CAS  PubMed  Google Scholar 

  17. Jolivalt CG, Lee CA, Ramos KM, Calcutt NA (2008) Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters. Pain 140:48–57. doi:https://doi.org/10.1016/j.pain.2008.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nomura H, Sakai A, Nagano M, Umino M, Suzuki H (2006) Expression of change of cation chloride cotransporters in the rat spinal cord following intraplantar formalin. Neurosci Res 56:435–440. doi:https://doi.org/10.1016/j.neures.2006.08.012

    Article  CAS  PubMed  Google Scholar 

  19. Tsuruga K, Hashimoto T, Kato R, Kato R, Uchida Y, Hase T, Morimoto Y (2016) Planter injection of formalin in rats reduces the expression of a potassium chloride cotransporter KCC2 in the spinal cord and a kinase inhibitor suppresses this reduction. Biomed Res 37:243–249. doi:https://doi.org/10.2220/biomedres.37.243

    Article  CAS  PubMed  Google Scholar 

  20. Zhang W, Liu LY, Xu TL (2008) Reduced potassium-chloride co-transporter expression in spinal cord dorsal horn neurons contributes to inflammatory pain hypersensitivity in rats. Neuroscience 152:502–510. doi:https://doi.org/10.1016/j.neuroscience.2007.12.037

    Article  CAS  PubMed  Google Scholar 

  21. Li YQ, Li H, Wei J, Qu L, Wu LA (2010) Expression changes of K+-Cl co-transporter 2 and Na+-K+-Cl co-transporter1 in mouse trigeminal subnucleus caudalis following pulpal inflammation. Brain Res Bull 81:561–564. doi:https://doi.org/10.1016/j.brainresbull.2010.01.002

    Article  CAS  PubMed  Google Scholar 

  22. Coull JAM, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, Koninck YD (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. doi:https://doi.org/10.1038/nature04223

    Article  CAS  PubMed  Google Scholar 

  23. Kitayama T (2016) Relationship between neuropathic pain and zinc ion. Glob Drugs Therap 1:1–2

    Article  Google Scholar 

  24. Buldyrev I, Tanner NM, Hsieh HY, Dodd EG, Nguyen LT, Balkowiec A (2006) Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons. J Neurochem 99:1338–1350. doi:https://doi.org/10.1111/j.1471-4159.2006.04161.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jantzie LL, Getsy PM, Firl DJ, Wilson CG, Miller RH, Robinson S (2014) Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury. Mol Cell Neurosci 61:152–162. doi:https://doi.org/10.1016/j.mcn.2014.06.009

    Article  CAS  PubMed  Google Scholar 

  26. Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, Lombroso PJ, Salter MW (2016) Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibitoni in spinal pain processing. Cell Rep 17:2753–2765. doi:https://doi.org/10.1016/j.celrep.2016.11.024

    Article  CAS  PubMed  Google Scholar 

  27. Vikman KS, Siddall PJ, Duggan AW (2005) Increase responsiveness of rat dorsal horn neurons in vivo following prolonged intrathecal exposure to interferon-γ. Neuroscience 135:969–977. doi:https://doi.org/10.1016/j.neuroscience.2005.06.059

    Article  CAS  PubMed  Google Scholar 

  28. Zelenka M, Schafers M, Sommer C (2005) Intraneural injection of interleukin-1β and tumor necrosis factor-α into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 116:257–263. doi:https://doi.org/10.1016/j.pain.2005.04.018

    Article  CAS  PubMed  Google Scholar 

  29. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early-and late-phase development of neuropathic pain. Nat Med 14:331–336. doi:https://doi.org/10.1038/nm1723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo LE, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu JM, Cahill CM, SalterMW, De Koninck Y (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl homeostasis. Nat Neurosci 16:183–192. doi:https://doi.org/10.1038/nn.3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, Tozaki-Saitoh H, Imai T, Kuraishi Y, Tsuda M, Inoue K (2016) A novel P2 × 4 receptor-selective antagonist produces anti-allodynic effect in amouse model of neuropathic pain. Sci Rep 31:32461. doi:https://doi.org/10.1038/srep32461

    Article  CAS  Google Scholar 

  32. Trang T, Beggs S, Wan X, Salter MW (2009) P2 × 4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29:3518–3528. doi:https://doi.org/10.1523/JNEUROSCI.5714-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Up-regulation of P2 × 4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268. doi:https://doi.org/10.1523/JNEUROSCI.2308-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yeo M, Berglund K, Augustine G, Liedtke W (2009) Nobel repression of KCC2 transcription by REST-RE-1 controls developmental switch in neuronal chloride. J Neurosci 29:14652–14662. doi:https://doi.org/10.1523/JNEUROSCI.2934-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Strange K, Singer TD, Morrison R, Delpire E (2000) Dependence of KCC2 K-Cl cotransporter activity on a conserved carboxy terminus tyrosine residue. Am J Cell Physiol 279:C860–C867

    Article  CAS  Google Scholar 

  36. Rinehart J, Maksimova YD, Tanis JE, Stone KI, Hodson CA, Zhang J, Risinger M, Pan W, Wu D, Colangelo CM, Forbush B, Joiner CH, Gulcicek EE, Gallagher PG, Lifton RP (2009) Site of regulated phosphorylation that control K-Cl cotransporter activity. Cell 138:525–536. doi:https://doi.org/10.1016/j.cell.2009.05.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Banke TG, Gegelashvili G (2008) Tonic activation of grupâ I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity. J Physiol 586:4925–4934. doi:https://doi.org/10.1113/jphysiol.2008.157024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wake H, Watanabe M, Moorhouse AJ, Kanematsu T, Horibe S, Matsukawa N, Asai K, Ojika K, Hirata M, Nabekura J (2007) Early changes in KCC2 phosphorylation in response to neuronal stress result in functional down-regulation. J Neurosci 27:1642–1650. doi:https://doi.org/10.1523/JNEUROSCI.3104-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Watanabe M, Wake H, Moorhouse AJ, Nabekura J (2009) Clustering of neuronal K+-Cl co-transporters in lipid refts by tyrosine phosphorylation. J Biol Chem 284:27980–27988. doi:https://doi.org/10.1074/jbc.M109.043620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chorin E, Vinogras O, Fleidervish I, Gilad D, Hermann S, Sekler I, Aizenman E, Hershfinkel M (2011) Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. J Neurosci 31:12916–12926. doi:https://doi.org/10.1523/JNEUROSCI.2205-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bos R, Sadlaoud K, Boulenguez P, Buttigieg D, Liabeuf S, Brocard C, Haase G, Bras H, Vinay L (2013) Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cptransporter KCC2. Proc Natl Acad Sci USA 110:348–353. doi:https://doi.org/10.1073/pnas.1213680110

    Article  CAS  PubMed  Google Scholar 

  42. Ford A, Castonguay A, Cottet M, Little JW, ChenZ, Symons-Liguori AM, Doyle T, Egan TM, Vanderah TW, De Konnick Y, Tosh DK, Jacobson KA, Salvemini D (2015) Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain. J Neurosci 35:6057–6067. doi:https://doi.org/10.1523/JNEUROSCI.4495-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hűbner CA, Represa A, Ben-Ari Y, Khazipov R (2006) Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314:1788–1792. doi:https://doi.org/10.1126/science.1133212

    Article  CAS  PubMed  Google Scholar 

  44. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, Ben-Ari Y (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343:675–679. doi:https://doi.org/10.1126/science.1247190

    Article  CAS  PubMed  Google Scholar 

  45. Lee HHC, Jurd R, Moss SJ (2010) Tyrosine phosphorylation regulates the membrane trafficking of the potassium chloride co-transporter KCC2. Mol Cell Neurosci 45:173–179. doi:https://doi.org/10.1016/j.mcn.2010.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Prescott SA, Sejnowski TJ, De Koninck Y (2006) Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain 2:32. doi:https://doi.org/10.1186/1744-8069-2-32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Abdin MJ, Morioka N, Morita K, Kitayama T, Kitayama S, Nakashima T, Dohi T (2006) Analgesic action of nicotine on tibial nerve transaction (TNT)-induced mechanical allodynia through enhancement of the glycinergic inhibitory system in spinal cord. Life Sci 80:9–16. doi:https://doi.org/10.1016/j.lfs.2006.08.011

    Article  CAS  PubMed  Google Scholar 

  48. Brasnjo G, Otis TS (2003) Glycine transporters not only take out the garbage, they recycle. Neuron 40:667–669

    Article  CAS  PubMed  Google Scholar 

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Kitayama, T. The Role of K+-Cl-Cotransporter-2 in Neuropathic Pain. Neurochem Res 43, 110–115 (2018). https://doi.org/10.1007/s11064-017-2344-3

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