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Ion channel long non-coding RNAs in neuropathic pain

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Abstract

Neuropathic pain is one of the primary forms of chronic pain and is the consequence of the somatosensory system’s direct injury or disease. It is a relevant public health problem that affects about 10% of the world’s general population. In neuropathic pain, alteration in neurotransmission occurs at various levels, including the dorsal root ganglia, the spinal cord, and the brain, resulting from the malfunction of diverse molecules such as receptors, ion channels, and elements of specific intracellular signaling pathways. In this context, there have been exciting advances in elucidating neuropathic pain’s cellular and molecular mechanisms in the last decade, including the possible role that long non-coding RNAs (lncRNAs) may play, which open up new alternatives for the development of diagnostic and therapeutic strategies for this condition. This review focuses on recent studies associated with the possible relevance of lncRNAs in the development and maintenance of neuropathic pain through their actions on the functional expression of ion channels. Recognizing the changes in the function and spatio-temporal patterns of expression of these membrane proteins is crucial to understanding the control of neuronal excitability in chronic pain syndromes.

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References

  1. Abd-Elsayed A, Jackson M, Gu SL, Fiala K, Gu J (2019) Neuropathic pain and Kv7 voltage-gated potassium channels: the potential role of Kv7 activators in the treatment of neuropathic pain. Mol Pain 15:1744806919864256. https://doi.org/10.1177/1744806919864256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Albuquerque EX, Pereira EF, Castro NG, Alkondon M, Reinhardt S, Schroder H, Maelicke A (1995) Nicotinic receptor function in the mammalian central nervous system. Ann N Y Acad Sci 757:48–72. https://doi.org/10.1111/j.1749-6632.1995.tb17464.x

    Article  CAS  PubMed  Google Scholar 

  3. Alles SRA, Cain SM, Snutch TP (2020) Pregabalin as a pain therapeutic: beyond calcium channels. Front Cell Neurosci 14:83. https://doi.org/10.3389/fncel.2020.00083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alles SRA, Smith PA (2018) Etiology and pharmacology of neuropathic pain. Pharmacol Rev 70:315–347. https://doi.org/10.1124/pr.117.014399

    Article  CAS  PubMed  Google Scholar 

  5. Andrade A, Sandoval A, González-Ramírez R, Lipscombe D, Campbell KP, Felix R (2009) The α2ẟ subunit augments functional expression and modifies the pharmacology of CaV1.3 L-type channels. Cell Calcium 46:282–292. https://doi.org/10.1016/j.ceca.2009.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Arun G, Diermeier SD, Spector DL (2018) Therapeutic targeting of long non-coding RNAs in cancer. Trends Mol Med 24:257–277. https://doi.org/10.1016/j.molmed.2018.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baron R, Binder A, Wasner G (2010) Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 9:807–819. https://doi.org/10.1016/s1474-4422(10)70143-5

    Article  PubMed  Google Scholar 

  8. Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, Kadurin I, Sri Ranjan Y, Fernandez-Alacid L, Millar NS, Dickenson AH, Lujan R, Dolphin AC (2009) The increased trafficking of the calcium channel subunit α2ẟ-1 to presynaptic terminals in neuropathic pain is inhibited by the α2ẟ ligand pregabalin. J Neurosci 29:4076–4088. https://doi.org/10.1523/jneurosci.0356-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beermann J, Piccoli MT, Viereck J, Thum T (2016) Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev 96:1297–1325. https://doi.org/10.1152/physrev.00041.2015

    Article  CAS  PubMed  Google Scholar 

  10. Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD (2019) The role of voltage-gated sodium channels in pain signaling. Physiol Rev 99:1079–1151. https://doi.org/10.1152/physrev.00052.2017

    Article  CAS  PubMed  Google Scholar 

  11. Bevan S, Andersson DA (2009) TRP channel antagonists for pain–opportunities beyond TRPV1. Curr Opin Investig Drugs 10:655–663

    CAS  PubMed  Google Scholar 

  12. Boroujerdi A, Kim HK, Lyu YS, Kim DS, Figueroa KW, Chung JM, Luo DZ (2008) Injury discharges regulate calcium channel α2ẟ-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain. Pain 139:358–366. https://doi.org/10.1016/j.pain.2008.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boroujerdi A, Zeng J, Sharp K, Kim D, Steward O, Luo DZ (2011) Calcium channel α2ẟ-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states. Pain 152:649–655. https://doi.org/10.1016/j.pain.2010.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C (2008) Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136:380–387. https://doi.org/10.1016/j.pain.2007.08.013

    Article  PubMed  Google Scholar 

  15. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW (2014) Calcium-permeable ion channels in pain signaling. Physiol Rev 94:81–140. https://doi.org/10.1152/physrev.00023.2013

    Article  CAS  PubMed  Google Scholar 

  16. Bourinet E, Francois A, Laffray S (2016) T-type calcium channels in neuropathic pain. Pain 157(Suppl 1):S15-s22. https://doi.org/10.1097/j.pain.0000000000000469

    Article  PubMed  Google Scholar 

  17. Campbell JN, Meyer RA (2006) Mechanisms of neuropathic pain. Neuron 52:77–92. https://doi.org/10.1016/j.neuron.2006.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Catterall WA, Lenaeus MJ, Gamal El-Din TM (2020) Structure and pharmacology of voltage-gated sodium and calcium channels. Annu Rev Pharmacol Toxicol 60:133–154. https://doi.org/10.1146/annurev-pharmtox-010818-021757

    Article  CAS  PubMed  Google Scholar 

  19. Chen L, Huang J, Zhao P, Persson AK, Dib-Hajj FB, Cheng X, Tan A, Waxman SG, Dib-Hajj SD (2018) Conditional knockout of NaV1.6 in adult mice ameliorates neuropathic pain. Sci Rep 8:3845. https://doi.org/10.1038/s41598-018-22216-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chizh BA, O’Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM (2007) The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 132:132–141. https://doi.org/10.1016/j.pain.2007.06.006

    Article  CAS  PubMed  Google Scholar 

  21. Chua HC, Chebib M (2017) GABAA Receptors and the diversity in their structure and pharmacology. Adv Pharmacol 79:1–34. https://doi.org/10.1016/bs.apha.2017.03.003

    Article  CAS  PubMed  Google Scholar 

  22. Cohen SP, Mao J (2014) Neuropathic pain: mechanisms and their clinical implications. BMJ 348:f7656. https://doi.org/10.1136/bmj.f7656

    Article  PubMed  Google Scholar 

  23. Cohen SP, Vase L, Hooten WM (2021) Chronic pain: an update on burden, best practices and new advances. Lancet 397(10289):2082–2097. https://doi.org/10.1016/S0140-6736(21)00393-7

    Article  PubMed  Google Scholar 

  24. Corney BPA, Widnall CL, Rees DJ, Davies JS, Crunelli V, Carter DA (2019) Regulatory architecture of the neuronal Cacng2/Tarpγ2 gene promoter: multiple repressive domains, a polymorphic regulatory short tandem repeat, and bidirectional organization with co-regulated lncRNAs. J Mol Neurosci 67:282–294. https://doi.org/10.1007/s12031-018-1208-x

    Article  CAS  PubMed  Google Scholar 

  25. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894–898. https://doi.org/10.1038/nature05413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cregg R, Momin A, Rugiero F, Wood JN, Zhao J (2010) Pain channelopathies. J Physiol 588:1897–1904. https://doi.org/10.1113/jphysiol.2010.187807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Delás MJ, Hannon GJ (2017) lncRNAs in development and disease: from functions to mechanisms. Open Biol 7. https://doi.org/10.1098/rsob.170121

  28. Delgado-Lezama R, Bravo-Hernández M, Franco-Enzástiga Ú, De la Luz-Cuellar YE, Alvarado-Cervantes NS, Raya-Tafolla G, Martínez-Zaldivar LA, Vargas-Parada A, Rodríguez-Palma EJ, Vidal-Cantú GC, Guzmán-Priego CG, Torres-López JE, Murbartián J, Felix R, Granados-Soto V (2021) The role of spinal cord extrasynaptic α5 GABAA receptors in chronic pain. Physiol Rep. 9(16):e14984. https://doi.org/10.14814/phy2.14984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789. https://doi.org/10.1101/gr.132159.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Devor M (1991) Neuropathic pain and injured nerve: peripheral mechanisms. Br Med Bull 47:619–630. https://doi.org/10.1093/oxfordjournals.bmb.a072496

    Article  CAS  PubMed  Google Scholar 

  31. Devor M (2006) Chapter 19 Pathophysiology of nerve injury. Handb Clin Neurol 81:261–iv. https://doi.org/10.1016/s0072-9752(06)80023-0

    Article  PubMed  Google Scholar 

  32. Devor M (2006) Sodium channels and mechanisms of neuropathic pain. J Pain. 7(1 Suppl 1):S3–S12. https://doi.org/10.1016/j.jpain.2005.09.006

    Article  CAS  PubMed  Google Scholar 

  33. Devor M (2009) Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 196:115–128. https://doi.org/10.1007/s00221-009-1724-6

    Article  CAS  PubMed  Google Scholar 

  34. Dib-Hajj SD, Yang Y, Black JA, Waxman SG (2013) The NaV1.7 sodium channel: from molecule to man. Nat Rev Neurosci 14:49–62. https://doi.org/10.1038/nrn3404

    Article  CAS  PubMed  Google Scholar 

  35. Felix R (2006) Calcium channelopathies. Neuromolecular Med 8:307–318. https://doi.org/10.1385/nmm:8:3:307

    Article  CAS  PubMed  Google Scholar 

  36. Felix R, Calderón-Rivera A, Andrade A (2013) Regulation of high-voltage-activated Ca2+ channel function, trafficking, and membrane stability by auxiliary subunits. Wiley Interdiscip Rev Membr Transp Signal 2:207–220. https://doi.org/10.1002/wmts.93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fernandes JCR, Acuña SM, Aoki JI, Floeter-Winter LM, Muxel SM (2019) Long non-coding rnas in the regulation of gene expression: physiology and disease. Noncoding RNA 5. https://doi.org/10.3390/ncrna5010017

  38. Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M (2006) SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52:767–774. https://doi.org/10.1016/j.neuron.2006.10.006

    Article  CAS  PubMed  Google Scholar 

  39. Gada K, Plant LD (2019) Two-pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26. Br J Pharmacol 176:256–266. https://doi.org/10.1111/bph.14518

    Article  CAS  PubMed  Google Scholar 

  40. Gandini MA, Felix R (2015) Molecular and functional interplay of voltage-gated Ca2+ channels with the cytoskeleton. Curr Mol Pharmacol 8:69-80. 10.2174/1874467208666150507094252

  41. García-Caballero A, Gadotti VM, Stemkowski P, Weiss N, Souza IA, Hodgkinson V, Bladen C, Chen L, Hamid J, Pizzoccaro A, Deage M, François A, Bourinet E, Zamponi GW (2014) The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity. Neuron 83:1144–1158. https://doi.org/10.1016/j.neuron.2014.07.036

    Article  CAS  PubMed  Google Scholar 

  42. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2ẟ subunit of a calcium channel. J Biol Chem 271:5768–5776. https://doi.org/10.1074/jbc.271.10.5768

    Article  CAS  PubMed  Google Scholar 

  43. Gibbons A, Udawela M, Dean B (2018) Non-coding RNA as novel players in the pathophysiology of schizophrenia. Noncoding RNA 4. https://doi.org/10.3390/ncrna4020011

  44. Gierthmühlen J, Baron R (2016) Neuropathic Pain. Semin Neurol 36:462–468. https://doi.org/10.1055/s-0036-1584950

    Article  PubMed  Google Scholar 

  45. Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J (2003) Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci 23:158–166. https://doi.org/10.1523/JNEUROSCI.23-01-00158.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gomez K, Calderón-Rivera A, Sandoval A, González-Ramírez R, Vargas-Parada A, Ojeda-Alonso J, Granados-Soto V, Delgado-Lezama R, Felix R (2020) Cdk5-Dependent phosphorylation of CaV3.2 T-type channels: possible role in nerve ligation-induced neuropathic allodynia and the compound action potential in primary afferent C fibers. J Neurosci 40:283–296. https://doi.org/10.1523/jneurosci.0181-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gómez K, Sandoval A, Barragán-Iglesias P, Granados-Soto V, Delgado-Lezama R, Felix R, González-Ramírez R (2019) Transcription factor Sp1 regulates the expression of calcium channel α2δ-1 subunit in neuropathic pain. Neuroscience 412:207–215. https://doi.org/10.1016/j.neuroscience.2019.06.011

    Article  CAS  PubMed  Google Scholar 

  48. Gomez K, Vargas-Parada A, Duran P, Sandoval A, Delgado-Lezama R, Khanna R, Felix R (2021) L5–6 spinal nerve ligation-induced neuropathy changes the location and function of Ca2+ channels and Cdk5 and affects the compound action potential in adjacent intact L4 afferent fibers. Neuroscience. 471:20–31. https://doi.org/10.1016/j.neuroscience.2021.07.013

    Article  CAS  PubMed  Google Scholar 

  49. González-Ramírez R, Chen Y, Liedtke WB, Morales-Lázaro SL. TRP channels and pain. In: Emir TLR, editor. Neurobiology of TRP Channels. Boca Raton (FL): CRC Press/Taylor & Francis; 2017. Chapter 8. https://doi.org/10.4324/9781315152837-8

  50. Goodwin G, McMahon SB (2021) The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci 22:263–274. https://doi.org/10.1038/s41583-021-00444-w

    Article  CAS  PubMed  Google Scholar 

  51. Guo X, Gao L, Liao Q, Xiao H, Ma X, Yang X, Luo H, Zhao G, Bu D, Jiao F, Shao Q, Chen R, Zhao Y (2013) Long non-coding RNAs function annotation: a global prediction method based on bi-colored networks. Nucleic Acids Res 41:e35. https://doi.org/10.1093/nar/gks967

    Article  CAS  PubMed  Google Scholar 

  52. Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482:339–346. https://doi.org/10.1038/nature10887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hendrich J, Van Minh AT, Heblich F, Nieto-Rostro M, Watschinger K, Striessnig J, Wratten J, Davies A, Dolphin AC (2008) Pharmacological disruption of calcium channel trafficking by the α2ẟ ligand gabapentin. Proc Natl Acad Sci U S A 105:3628–3633. https://doi.org/10.1073/pnas.0708930105

    Article  PubMed  PubMed Central  Google Scholar 

  54. Henry MA, Freking AR, Johnson LR, Levinson SR (2007) Sodium channel Nav1.6 accumulates at the site of infraorbital nerve injury. BMC Neurosci 8:56. https://doi.org/10.1186/1471-2202-8-56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hombach S, Kretz M (2016) Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol 937:3–17. https://doi.org/10.1007/978-3-319-42059-2_1

    Article  CAS  PubMed  Google Scholar 

  56. Honore P, Wismer CT, Mikusa J, Zhu CZ, Zhong C, Gauvin DM, Gomtsyan A, El Kouhen R, Lee CH, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF (2005) A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J Pharmacol Exp Ther 314:410–421. https://doi.org/10.1124/jpet.105.083915

    Article  CAS  PubMed  Google Scholar 

  57. Hosseini E, Bagheri-Hosseinabadi Z, De Toma I, Jafarisani M, Sadeghi I (2019) The importance of long non-coding RNAs in neuropsychiatric disorders. Mol Aspects Med 70:127–140. https://doi.org/10.1016/j.mam.2019.07.004

    Article  CAS  PubMed  Google Scholar 

  58. Imbrici P, Liantonio A, Camerino GM, De Bellis M, Camerino C, Mele A, Giustino A, Pierno S, De Luca A, Tricarico D, Desaphy JF, Conte D (2016) Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery. Front Pharmacol 7:121. https://doi.org/10.3389/fphar.2016.00121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jaggi AS, Jain V, Singh N (2011) Animal models of neuropathic pain. Fundam Clin Pharmacol 25:1–28. https://doi.org/10.1111/j.1472-8206.2009.00801.x

    Article  CAS  PubMed  Google Scholar 

  60. Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, Su P, Jevtovic-Todorovic V, Todorovic SM (2008) Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 99:3151–3156. https://doi.org/10.1152/jn.01031.2007

    Article  CAS  PubMed  Google Scholar 

  61. Jara-Oseguera A, Simon SA, Rosenbaum T (2008) TRPV1: on the road to pain relief. Curr Mol Pharmacol 1(3):255–269. https://doi.org/10.2174/1874467210801030255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jentsch TJ, Pusch M (2018) CLC chloride channels and transporters: structure, function, physiology, and disease. Physiol Rev 98:1493–1590. https://doi.org/10.1152/physrev.00047.2017

    Article  CAS  PubMed  Google Scholar 

  63. Jiang BC, Sun WX, He LN, Cao DL, Zhang ZJ, Gao YJ (2015) Identification of lncRNA expression profile in the spinal cord of mice following spinal nerve ligation-induced neuropathic pain. Mol Pain 11:43. https://doi.org/10.1186/s12990-015-0047-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (2012) Molecular and functional properties of P2X receptors–recent progress and persisting challenges. Purinergic Signal 8:375–417. https://doi.org/10.1007/s11302-012-9314-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kalpachidou T, Kummer KK, Kress M (2020) Non-coding RNAs in neuropathic pain. Neuronal Signal 4:Ns20190099. https://doi.org/10.1042/ns20190099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kang MG, Chen CC, Felix R, Letts VA, Frankel WN, Mori Y, Campbell KP (2001) Biochemical and biophysical evidence for γ2 subunit association with neuronal voltage-activated Ca2+ channels. J Biol Chem 276:32917–32924. https://doi.org/10.1074/jbc.M100787200

    Article  CAS  PubMed  Google Scholar 

  67. Kim CH, Oh Y, Chung JM, Chung K (2002) Changes in three subtypes of tetrodotoxin sensitive sodium channel expression in the axotomized dorsal root ganglion in the rat. Neurosci Lett 323:125–128. https://doi.org/10.1016/s0304-3940(02)00127-1

    Article  CAS  PubMed  Google Scholar 

  68. Koenig J, Werdehausen R, Linley JE, Habib AM, Vernon J, Lolignier S, Eijkelkamp N, Zhao J, Okorokov AL, Woods CG, Wood JN, Cox JJ (2015) Regulation of NaV1.7: a conserved SCN9A natural antisense transcript expressed in dorsal root ganglia. PLoS One 10:e0128830. https://doi.org/10.1371/journal.pone.0128830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kong C, Du J, Bu H, Huang C, Xu F, Ren H (2020) LncRNA KCNA2-AS regulates spinal astrocyte activation through STAT3 to affect postherpetic neuralgia. Mol Med 26:113. https://doi.org/10.1186/s10020-020-00232-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, Woods CG, Jones NG, Paterson KJ, Fricker FR, Villegas A, Acosta N, Pineda-Trujillo NG, Ramírez JD, Zea J, Burley MW, Bedoya G, Bennett DL, Wood JN, Ruiz-Linares A (2010) A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66:671–680. https://doi.org/10.1016/j.neuron.2010.04.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA (2005) International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev 57:509–526. https://doi.org/10.1124/pr.57.4.11

    Article  CAS  PubMed  Google Scholar 

  72. Kung JT, Colognori D, Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193:651–669. https://doi.org/10.1534/genetics.112.146704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Letts VA (2005) Stargazer–a mouse to seize! Epilepsy Curr 5:161–165. https://doi.org/10.1111/j.1535-7511.2005.00051.x

    Article  PubMed  PubMed Central  Google Scholar 

  74. Letts VA, Felix R, Biddlecome GH, Arikkath J, Mahaffey CL, Valenzuela A, Bartlett FS 2nd, Mori Y, Campbell KP, Frankel WN (1998) The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat Genet 19:340–347. https://doi.org/10.1038/1228

    Article  CAS  PubMed  Google Scholar 

  75. Li CY, Song YH, Higuera ES, Luo ZD (2004) Spinal dorsal horn calcium channel α2ẟ-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci 24:8494–8499. https://doi.org/10.1523/jneurosci.2982-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li G, Jiang H, Zheng C, Zhu G, Xu Y, Sheng X, Wu B, Guo J, Zhu S, Zhan Y, Lin W, Ding R, Zhang C, Liu S, Zou L, Yi Z, Liang S (2017) Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats. Pain 158:2042–2052. https://doi.org/10.1097/j.pain.0000000000001013

    Article  CAS  PubMed  Google Scholar 

  77. Li J, Tian H, Yang J, Gong Z (2016) Long noncoding RNAs regulate cell growth, proliferation, and apoptosis. DNA Cell Biol 35:459–470. https://doi.org/10.1089/dna.2015.3187

    Article  CAS  PubMed  Google Scholar 

  78. Li Z, Li X, Chen X, Li S, Ho IHT, Liu X, Chan MTV, Wu WKK (2019) Emerging roles of long non-coding RNAs in neuropathic pain. Cell Prolif 52:e12528. https://doi.org/10.1111/cpr.12528

    Article  PubMed  Google Scholar 

  79. Liang L, Gu X, Zhao JY, Wu S, Miao X, Xiao J, Mo K, Zhang J, Lutz BM, Bekker A, Tao YX (2016) G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci Rep 6:37704. https://doi.org/10.1038/srep37704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu C, Li C, Deng Z, Du E, Xu C (2018) Long non-coding RNA BC168687 is involved in TRPV1-mediated diabetic neuropathic pain in rats. Neuroscience 374:214–222. https://doi.org/10.1016/j.neuroscience.2018.01.049

    Article  CAS  PubMed  Google Scholar 

  81. Liu C, Tao J, Wu H, Yang Y, Chen Q, Deng Z, Liu J, Xu C (2017) Effects of LncRNA BC168687 siRNA on diabetic neuropathic pain mediated by P2X(7) receptor on SGCs in DRG of rats. Biomed Res Int 2017:7831251. https://doi.org/10.1155/2017/7831251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu S, Zou L, Xie J, Xie W, Wen S, Xie Q, Gao Y, Li G, Zhang C, Xu C, Xu H, Wu B, Lv Q, Zhang X, Wang S, Xue Y, Liang S (2016) LncRNA NONRATT021972 siRNA regulates neuropathic pain behaviors in type 2 diabetic rats through the P2X7 receptor in dorsal root ganglia. Mol Brain 9:44. https://doi.org/10.1186/s13041-016-0226-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Liu Z, Liang Y, Wang H, Lu Z, Chen J, Huang Q, Sheng L, Ma Y, Du H, Gong Q (2017) LncRNA expression in the spinal cord modulated by minocycline in a mouse model of spared nerve injury. J Pain Res 10:2503–2514. https://doi.org/10.2147/jpr.S147055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, Yaksh TL (2001) Upregulation of dorsal root ganglion α2ẟ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 21:1868–1875. https://doi.org/10.1523/jneurosci.21-06-01868.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Margas W, Ferron L, Nieto-Rostro M, Schwartz A, Dolphin AC (2016) Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons. Philos Trans R Soc Lond B Biol Sci 371. https://doi.org/10.1098/rstb.2015.0430

  86. Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Manocchio L, Medoro A, Taglialatela M (2015) Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels. Front Cell Neurosci 9:259. https://doi.org/10.3389/fncel.2015.00259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Newton RA, Bingham S, Case PC, Sanger GJ, Lawson SN (2001) Dorsal root ganglion neurons show increased expression of the calcium channel α2ẟ-1 subunit following partial sciatic nerve injury. Brain Res Mol Brain Res 95:1–8. https://doi.org/10.1016/s0169-328x(01)00188-7

    Article  CAS  PubMed  Google Scholar 

  88. Nishiyama T (2000) Interaction among NMDA receptor-, NMDA glycine site- and AMPA receptor antagonists in spinally mediated analgesia. Can J Anaesth 47:693–698. https://doi.org/10.1007/bf03019004

    Article  CAS  PubMed  Google Scholar 

  89. Nissenbaum J (2012) From mouse to humans: discovery of the CACNG2 pain susceptibility gene. Clin Genet 82:311–320. https://doi.org/10.1111/j.1399-0004.2012.01924.x

    Article  CAS  PubMed  Google Scholar 

  90. Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisanté A, Darvasi A (2010) Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 20:1180–1190. https://doi.org/10.1101/gr.104976.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Novikova IV, Hennelly SP, Tung CS, Sanbonmatsu KY (2013) Rise of the RNA machines: exploring the structure of long non-coding RNAs. J Mol Biol 425:3731–3746. https://doi.org/10.1016/j.jmb.2013.02.030

    Article  CAS  PubMed  Google Scholar 

  92. Ong CT, Corces VG (2011) Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12:283–293. https://doi.org/10.1038/nrg2957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang C, Wang X, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY, Weyer AD, Dekan Z, Undheim EA, Alewood P, Stucky CL, Brierley SM, Basbaum AI, Bosmans F, King GF, Julius D (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534:494–499. https://doi.org/10.1038/nature17976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400. https://doi.org/10.1038/nrn3504

    Article  CAS  PubMed  Google Scholar 

  95. Patel R, Bauer CS, Nieto-Rostro M, Margas W, Ferron L, Chaggar K, Crews K, Ramirez JD, Bennett DL, Schwartz A, Dickenson AH, Dolphin AC (2013) α2δ-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage. J Neurosci 33:16412–16426. https://doi.org/10.1523/jneurosci.1026-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Peng H, Zou L, Xie J, Wu H, Wu B, Zhu G, Lv Q, Zhang X, Liu S, Li G, Xu H, Gao Y, Xu C, Zhang C, Wang S, Xue Y, Liang S (2017) lncRNA NONRATT021972 siRNA decreases diabetic neuropathic pain mediated by the P2X(3) Receptor in dorsal root ganglia. Mol Neurobiol 54:511–523. https://doi.org/10.1007/s12035-015-9632-1

    Article  CAS  PubMed  Google Scholar 

  97. Perkins JR, Antunes-Martins A, Calvo M, Grist J, Rust W, Schmid R, Hildebrandt T, Kohl M, Orengo C, McMahon SB, Bennett DL (2014) A comparison of RNA-seq and exon arrays for whole genome transcription profiling of the L5 spinal nerve transection model of neuropathic pain in the rat. Mol Pain 10:7. https://doi.org/10.1186/1744-8069-10-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rogers M, Tang L, Madge DJ, Stevens EB (2006) The role of sodium channels in neuropathic pain. Semin Cell Dev Biol 17:571–581. https://doi.org/10.1016/j.semcdb.2006.10.009

    Article  CAS  PubMed  Google Scholar 

  99. Roza C, Bernal L. (2022) Electrophysiological characterization of ectopic spontaneous discharge in axotomized and intact fibers upon nerve transection: a role in spontaneous pain? Pflugers Arch. Jan 28. 10.1007/s00424-021-02655-7.

  100. Salta E, De Strooper B (2012) Non-coding RNAs with essential roles in neurodegenerative disorders. Lancet Neurol 11:189–200. https://doi.org/10.1016/s1474-4422(11)70286-1

    Article  CAS  PubMed  Google Scholar 

  101. Sandoval A, Andrade A, Beedle AM, Campbell KP, Felix R (2007) Inhibition of recombinant N-type CaV channels by the γ2 subunit involves unfolded protein response (UPR)-dependent and UPR-independent mechanisms. J Neurosci 27:3317–3327. https://doi.org/10.1523/jneurosci.4566-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Santosh B, Varshney A, Yadava PK (2015) Non-coding RNAs: biological functions and applications. Cell Biochem Funct 33:14–22. https://doi.org/10.1002/cbf.3079

    Article  CAS  PubMed  Google Scholar 

  103. Smith PA (2020) K+ Channels in primary afferents and their role in nerve injury-induced pain. Front Cell Neurosci 14:566418. https://doi.org/10.3389/fncel.2020.566418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Stemkowski PL, Garcia-Caballero A, Gadotti VM, M’Dahoma S, Chen L, Souza IA, Zamponi GW (2017) Identification of interleukin-1 beta as a key mediator in the upregulation of CaV3.2-USP5 interactions in the pain pathway. Mol Pain 13:1744806917724698. https://doi.org/10.1177/1744806917724698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sumioka A (2013) Auxiliary subunits provide new insights into regulation of AMPA receptor trafficking. J Biochem 153:331–337. https://doi.org/10.1093/jb/mvt015

    Article  CAS  PubMed  Google Scholar 

  106. Tang S, Zhou J, Jing H, Liao M, Lin S, Huang Z, Huang T, Zhong J, HanbingWang, (2019) Functional roles of lncRNAs and its potential mechanisms in neuropathic pain. Clin Epigenetics 11:78. https://doi.org/10.1186/s13148-019-0671-8

    Article  PubMed  PubMed Central  Google Scholar 

  107. Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS (2003) Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J Cell Biol 161:805–816. https://doi.org/10.1083/jcb.200212116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635. https://doi.org/10.1212/01.wnl.0000282763.29778.59

    Article  CAS  PubMed  Google Scholar 

  109. Tsantoulas C, McMahon SB (2014) Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci 37(3):146–158. https://doi.org/10.1016/j.tins.2013.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tsantoulas C, Zhu L, Shaifta Y, Grist J, Ward JP, Raouf R, Michael GJ, McMahon SB (2012) Sensory neuron downregulation of the KV9.1 potassium channel subunit mediates neuropathic pain following nerve injury. J Neurosci 32:17502–17513. https://doi.org/10.1523/jneurosci.3561-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. van Loo KM, Schaub C, Pernhorst K, Yaari Y, Beck H, Schoch S, Becker AJ (2012) Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein-silencing transcription factor (REST). J Biol Chem 287:15489–15501. https://doi.org/10.1074/jbc.M111.310763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vega-Hernández A, Felix R (2002) Down-regulation of N-type voltage-activated Ca2+ channels by gabapentin. Cell Mol Neurobiol 22:185–190. https://doi.org/10.1023/a:1019865822069

    Article  PubMed  Google Scholar 

  113. Wang M, Offord J, Oxender DL, Su TZ (1999) Structural requirement of the calcium-channel subunit α2ẟ for gabapentin binding. Biochem J 342(Pt 2):313–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang S, Xu H, Zou L, Xie J, Wu H, Wu B, Yi Z, Lv Q, Zhang X, Ying M, Liu S, Li G, Gao Y, Xu C, Zhang C, Xue Y, Liang S (2016) LncRNA uc.48+ is involved in diabetic neuropathic pain mediated by the P2X3 receptor in the dorsal root ganglia. Purinergic Signal 12:139–148. https://doi.org/10.1007/s11302-015-9488-x

    Article  CAS  PubMed  Google Scholar 

  115. Wei W, Pelechano V, Järvelin AI, Steinmetz LM (2011) Functional consequences of bidirectional promoters. Trends Genet 27:267–276. https://doi.org/10.1016/j.tig.2011.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wilke BU, Kummer KK, Leitner MG, Kress M (2020) Chloride - the underrated ion in nociceptors. Front Neurosci 4:287. https://doi.org/10.3389/fnins.2020.00287

    Article  Google Scholar 

  117. Winkle M, El-Daly SM, Fabbri M, Calin GA (2021) Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov 20:629–651. https://doi.org/10.1038/s41573-021-00219-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wu S, Bono J, Tao YX (2019) Long noncoding RNA (lncRNA): a target in neuropathic pain. Expert Opin Ther Targets 23:15–20. https://doi.org/10.1080/14728222.2019.1550075

    Article  CAS  PubMed  Google Scholar 

  119. Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A 99:8360–8365. https://doi.org/10.1073/pnas.122231899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Xiong W, Tan M, Tong Z, Yin C, He L, Liu L, Shen Y, Guan S, Ge H, Li G, Liang S, Gao Y (2019) Effects of long non-coding RNA uc.48+ on pain transmission in trigeminal neuralgia. Brain Res Bull 147:92–100. https://doi.org/10.1016/j.brainresbull.2019.02.009

    Article  CAS  PubMed  Google Scholar 

  121. Xu GY, Li G, Liu N, Huang LY (2011) Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Mol Pain 7:60. https://doi.org/10.1186/1744-8069-7-60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Xu H, He L, Liu C, Tang L, Xu Y, Xiong M, Yang M, Fan Y, Hu F, Liu X, Ding L, Gao Y, Xu C, Li G, Liu S, Wu B, Zou L, Liang S (2016) LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells. Purinergic Signal 12:259–268. https://doi.org/10.1007/s11302-016-9500-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yu W, Zhao GQ, Cao RJ, Zhu ZH, Li K (2017) LncRNA NONRATT021972 was associated with neuropathic pain scoring in patients with type 2 diabetes. Behav Neurol 2017:2941297. https://doi.org/10.1155/2017/2941297

    Article  PubMed  PubMed Central  Google Scholar 

  124. Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67:821–870. https://doi.org/10.1124/pr.114.009654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhao X, Tang Z, Zhang H, Atianjoh FE, Zhao JY, Liang L, Wang W, Guan X, Kao SC, Tiwari V, Gao YJ, Hoffman PN, Cui H, Li M, Dong X, Tao YX (2013) A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci 16:1024–1031. https://doi.org/10.1038/nn.3438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zheng Q, Fang D, Liu M, Cai J, Wan Y, Han JS, Xing GG (2013) Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain 154:434–448. https://doi.org/10.1016/j.pain.2012.12.005

    Article  CAS  PubMed  Google Scholar 

  127. Zhou J, Fan Y, Chen H (2017) Analyses of long non-coding RNA and mRNA profiles in the spinal cord of rats using RNA sequencing during the progression of neuropathic pain in an SNI model. RNA Biol 14:1810–1826. https://doi.org/10.1080/15476286.2017.1371400

    Article  PubMed  PubMed Central  Google Scholar 

  128. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW (2007) Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447:855–858. https://doi.org/10.1038/nature05880

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cell Biology, Centre for Research and Advanced Studies (Cinvestav), 07360, Mexico City, Mexico

    Ricardo Felix, David Muñoz-Herrera & Alejandra Corzo-López

  2. Department of Physiology, Biophysics and Neuroscience, Cinvestav, Mexico

    Miriam Fernández-Gallardo

  3. Department of Molecular Biology and Histocompatibility, “Dr. Manuel Gea González” General Hospital, Mexico City, Mexico

    Margarita Leyva-Leyva & Ricardo González-Ramírez

  4. School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla, Mexico

    Alejandro Sandoval

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Felix, R., Muñoz-Herrera, D., Corzo-López, A. et al. Ion channel long non-coding RNAs in neuropathic pain. Pflugers Arch - Eur J Physiol 474, 457–468 (2022). https://doi.org/10.1007/s00424-022-02675-x

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