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Molecular Pain

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Open Access 01-12-2011 | Research

TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

Authors: Astrid Tulleuda, Barbara Cokic, Gerard Callejo, Barbara Saiani, Jordi Serra, Xavier Gasull

Published in: Molecular Pain | Issue 1/2011

Abstract

Background

Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K⁺ channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K_2P channels after peripheral axotomy in mammals.

Results

Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo.

Conclusions

In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability.

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Campbell JN, Meyer RA: Mechanisms of neuropathic pain. Neuron 2006, 52: 77–92. 10.1016/j.neuron.2006.09.021PubMedCentralPubMedCrossRef

Sandkuhler J: Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009, 89: 707–758. 10.1152/physrev.00025.2008PubMedCrossRef

Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33: 87–107. 10.1016/0304-3959(88)90209-6PubMedCrossRef

Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992, 50: 355–363. 10.1016/0304-3959(92)90041-9PubMedCrossRef

Basbaum AI, Bautista DM, Scherrer G, Julius D: Cellular and molecular mechanisms of pain. Cell 2009, 139: 267–284. 10.1016/j.cell.2009.09.028PubMedCentralPubMedCrossRef

Abdulla FA, Smith PA: Axotomy- and autotomy-induced changes in Ca2+ and K+ channel currents of rat dorsal root ganglion neurons. Journal of Neurophysiology 2001, 85: 644–658.PubMed

Abdulla FA, Smith PA: Axotomy- and autotomy-induced changes in the excitability of rat dorsal root ganglion neurons. Journal of Neurophysiology 2001, 85: 630–643.PubMed

Gasull X, Liao X, Dulin MF, Phelps C, Walters ET: Evidence that long-term hyperexcitability of the sensory neuron soma induced by nerve injury in Aplysia is adaptive. J Neurophysiol 2005, 94: 2218–2230. 10.1152/jn.00169.2005PubMedCrossRef

Ungless MA, Gasull X, Walters ET: Long-term alteration of S-type potassium current and passive membrane properties in aplysia sensory neurons following axotomy. J Neurophysiol 2002, 87: 2408–2420.PubMed

10.

Zhang JM, Donnelly DF, Song XJ, Lamotte RH: Axotomy increases the excitability of dorsal root ganglion cells with unmyelinated axons. J Neurophysiol 1997, 78: 2790–2794.PubMed

11.

Zheng JH, Walters ET, Song XJ: Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP. J Neurophysiol 2007, 97: 15–25. 10.1152/jn.00559.2006PubMedCrossRef

12.

Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M: A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J 1998, 17: 4283–4290. 10.1093/emboj/17.15.4283PubMedCentralPubMedCrossRef

13.

Bockenhauer D, Zilberberg N, Goldstein SA: KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci 2001, 4: 486–491.PubMed

14.

Goldstein SA, Bockenhauer D, O'Kelly I, Zilberberg N: Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2001, 2: 175–184.PubMedCrossRef

15.

Enyedi P, Czirják G: Molecular background of leak K+ currents: two-pore domain potassium channels. Physiological Reviews 2010, 90: 559–605. 10.1152/physrev.00029.2009PubMedCrossRef

16.

Yamamoto Y, Hatakeyama T, Taniguchi K: Immunohistochemical colocalization of TREK-1, TREK-2 and TRAAK with TRP channels in the trigeminal ganglion cells. Neuroscience Letters 2009, 454: 129–133. 10.1016/j.neulet.2009.02.069PubMedCrossRef

17.

Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA: Cns distribution of members of the two-pore-domain (KCNK) potassium channel family. Journal of Neuroscience 2001, 21: 7491–7505.PubMed

18.

Dobler T, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E, Döring F: TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. The Journal of Physiology 2007, 585: 867–879. 10.1113/jphysiol.2007.145649PubMedCentralPubMedCrossRef

19.

Kang D, Kim D: TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. Am J Physiol, Cell Physiol 2006, 291: C138–146. 10.1152/ajpcell.00629.2005PubMedCrossRef

20.

Alloui A, Zimmermann K, Mamet J, Duprat F, Noël J, Chemin J, Guy N, Blondeau N, Voilley N, Rubat-Coudert C, et al.: TREK-1, a K+ channel involved in polymodal pain perception. Embo J 2006, 25: 2368–2376. 10.1038/sj.emboj.7601116PubMedCentralPubMedCrossRef

21.

Noel J, Zimmermann K, Busserolles J, Deval E, Alloui A, Diochot S, Guy N, Borsotto M, Reeh P, Eschalier A, Lazdunski M: The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. Embo J 2009, 28: 1308–1318. 10.1038/emboj.2009.57PubMedCentralPubMedCrossRef

22.

Lafrenière RG, Cader MZ, Poulin J-F, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, Mclaughlan S, Dubé M-P, et al.: A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine 2010.

23.

Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D: Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci 2008, 11: 772–779. 10.1038/nn.2143PubMedCentralPubMedCrossRef

24.

Lennertz RC, Tsunozaki M, Bautista DM, Stucky CL: Physiological Basis of Tingling Paresthesia Evokedby Hydroxy-alpha-Sanshool. Journal of Neuroscience 2010, 30: 4353–4361. 10.1523/JNEUROSCI.4666-09.2010PubMedCentralPubMedCrossRef

25.

Sawyer CM, Carstens MI, Simons CT, Slack J, Mccluskey TS, Furrer S, Carstens E: Activation of Lumbar Spinal Wide-Dynamic Range Neurons by a Sanshool Derivative. Journal of Neurophysiology 2009, 101: 1742–1748. 10.1152/jn.91311.2008PubMedCentralPubMedCrossRef

26.

Titmus MJ, Faber DS: Axotomy-induced alterations in the electrophysiological characteristics of neurons. Prog Neurobiol 1990, 35: 1–51. 10.1016/0301-0082(90)90039-JPubMedCrossRef

27.

Flake NM, Lancaster E, Weinreich D, Gold MS: Absence of an association between axotomy-induced changes in sodium currents and excitability in DRG neurons from the adult rat. Pain 2004, 109: 471–480. 10.1016/j.pain.2004.02.024PubMedCrossRef

28.

Song XJ, Wang ZB, Gan Q, Walters ET: cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression. J Neurophysiol 2006, 95: 479–492.PubMedCrossRef

29.

Yoo S, Liu J, Sabbadini M, Au P, Xie GX, Yost CS: Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neurosci Lett 2009, 465: 79–84. 10.1016/j.neulet.2009.08.062PubMedCentralPubMedCrossRef

30.

Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, Yaksh TL: Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 2001, 21: 1868–1875.PubMed

31.

Ma C, LaMotte R: Enhanced excitability of dissociated primary sensory neurons after chronic compression of the dorsal root ganglion in the rat. Pain 2005, 113: 106–112. 10.1016/j.pain.2004.10.001PubMedCrossRef

32.

Kang D, Choe C, Kim D: Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. The Journal of Physiology 2005, 564: 103–116. 10.1113/jphysiol.2004.081059PubMedCentralPubMedCrossRef

33.

Seijffers R, Allchorne AJ, Woolf CJ: The transcription factor ATF-3 promotes neurite outgrowth. Molecular and Cellular Neuroscience 2006, 32: 143–154. 10.1016/j.mcn.2006.03.005PubMedCrossRef

34.

Seijffers R, Mills CD, Woolf CJ: ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration. J Neurosci 2007, 27: 7911–7920. 10.1523/JNEUROSCI.5313-06.2007PubMedCrossRef

35.

Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T, Noguchi K: Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Molecular and Cellular Neuroscience 2000, 15: 170–182. 10.1006/mcne.1999.0814PubMedCrossRef

36.

Stam FJ, MacGillavry HD, Armstrong NJ, de Gunst MCM, Zhang Y, van Kesteren RE, Smit AB, Verhaagen J: Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury. Eur J Neurosci 2007, 25: 3629–3637. 10.1111/j.1460-9568.2007.05597.xPubMedCrossRef

37.

Aoki Y, An HS, Takahashi K, Miyamoto K, Lenz ME, Moriya H, Masuda K: Axonal growth potential of lumbar dorsal root ganglion neurons in an organ culture system: response of nerve growth factor-sensitive neurons to neuronal injury and an inflammatory cytokine. Spine 2007, 32: 857–863. 10.1097/01.brs.0000259810.48681.90PubMedCrossRef

38.

Albin KC, Simons CT: Psychophysical evaluation of a sanshool derivative (alkylamide) and the elucidation of mechanisms subserving tingle. PLoS ONE 2010, 5: e9520. 10.1371/journal.pone.0009520PubMedCentralPubMedCrossRef

39.

Kang D, Kim G-T, Kim E-J, La J-H, Lee J-S, Lee E-S, Park J-Y, Hong S-G, Han J: Lamotrigine inhibits TRESK regulated by G-protein coupled receptor agonists. Biochemical and Biophysical Research Communications 2008, 367: 609–615. 10.1016/j.bbrc.2008.01.008PubMedCrossRef

40.

Serra J, Campero M, Bostock H, Ochoa J: Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia. J Neurophysiol 2004, 91: 2770–2781. 10.1152/jn.00565.2003PubMedCrossRef

41.

Bedi SS, Cai D, Glanzman DL: Effects of Axotomy on Cultured Sensory Neurons of Aplysia: Long-Term Injury-Induced Changes in Excitability and Morphology Are Mediated by Different Signaling Pathways. Journal of Neurophysiology 2008, 100: 3209–3224. 10.1152/jn.90539.2008PubMedCentralPubMedCrossRef

42.

Liu B, Eisenach JC: Hyperexcitability of axotomized and neighboring unaxotomized sensory neurons is reduced days after perineural clonidine at the site of injury. Journal of Neurophysiology 2005, 94: 3159–3167. 10.1152/jn.00623.2005PubMedCrossRef

43.

Ma C, Shu Y, Zheng Z, Chen Y, Yao H, Greenquist KW, White FA, LaMotte RH: Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. Journal of Neurophysiology 2003, 89: 1588–1602.PubMedCrossRef

44.

Liu CN, Raber P, Ziv-Sefer S, Devor M: Hyperexcitability in sensory neurons of rats selected for high versus low neuropathic pain phenotype. Neuroscience 2001, 105: 265–275. 10.1016/S0306-4522(01)00161-0PubMedCrossRef

45.

Hucho T, Levine JD: Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 2007, 55: 365–376. 10.1016/j.neuron.2007.07.008PubMedCrossRef

46.

Delmas P: SnapShot: ion channels and pain. Cell 2008, 134: 366–366. e361 10.1016/j.cell.2008.07.006PubMedCrossRef

47.

Abdulla FA, Smith PA: Changes in Na(+) channel currents of rat dorsal root ganglion neurons following axotomy and axotomy-induced autotomy. Journal of Neurophysiology 2002, 88: 2518–2529. 10.1152/jn.00913.2001PubMedCrossRef

48.

André S, Boukhaddaoui H, Campo B, Al-Jumaily M, Mayeux V, Greuet D, Valmier J, Scamps F: Axotomy-induced expression of calcium-activated chloride current in subpopulations of mouse dorsal root ganglion neurons. Journal of Neurophysiology 2003, 90: 3764–3773. 10.1152/jn.00449.2003PubMedCrossRef

49.

Xiao H-S, Huang Q-H, Zhang F-X, Bao L, Lu Y-J, Guo C, Yang L, Huang W-J, Fu G, Xu S-H, et al.: Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci USA 2002, 99: 8360–8365. 10.1073/pnas.122231899PubMedCentralPubMedCrossRef

50.

Yang E-K, Takimoto K, Hayashi Y, de Groat WC, Yoshimura N: Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy. Neuroscience 2004, 123: 867–874. 10.1016/j.neuroscience.2003.11.014PubMedCrossRef

51.

Yang L, Zhang F-X, Huang F, Lu Y-J, Li G-D, Bao L, Xiao H-S, Zhang X: Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J Neurosci 2004, 19: 871–883. 10.1111/j.0953-816X.2004.03121.xPubMedCrossRef

52.

Rasband MN, Park EW, Vanderah TW, Lai J, Porreca F, Trimmer JS: Distinct potassium channels on pain-sensing neurons. Proc Natl Acad Sci USA 2001, 98: 13373–13378. 10.1073/pnas.231376298PubMedCentralPubMedCrossRef

53.

Nuwer MO, Picchione KE, Bhattacharjee A: PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. J Neurosci 2010, 30: 14165–14172. 10.1523/JNEUROSCI.3150-10.2010PubMedCrossRef

54.

Riera CE, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon SA, le Coutre J: Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Br J Pharmacol 2009, 157: 1398–1409. 10.1111/j.1476-5381.2009.00307.xPubMedCentralPubMedCrossRef

55.

Klein AH, Sawyer CM, Zanotto KL, Ivanov MA, Cheung S, Iodi Carstens M, Furrer S, Simons CT, Slack JP, Carstens E: A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats. J Neurophysiol 2011, 105: 1689–1700. 10.1152/jn.00981.2010CrossRef

56.

Koo JY, Jang Y, Cho H, Lee C-H, Jang KH, Chang YH, Shin J, Oh U: Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur J Neurosci 2007, 26: 1139–1147. 10.1111/j.1460-9568.2007.05743.xPubMedCrossRef

57.

Serra J, Bostock H, Navarro X: Microneurography in rats: a minimally invasive method to record single C-fiber action potentials from peripheral nerves in vivo. Neurosci Lett 2010, 470: 168–174. 10.1016/j.neulet.2009.09.061PubMedCrossRef

58.

Serra J, Solà R, Aleu J, Quiles C, Navarro X, Bostock H: Double and triple spikes in C-nociceptors in neuropathic pain states: an additional peripheral mechanism of hyperalgesia. Pain 2010.

59.

Schmelz M, Schmid R, Handwerker HO, Torebjork HE: Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 2000,123(Pt 3):560–571.PubMedCrossRef

60.

Schmidt R, Schmelz M, Torebjork HE, Handwerker HO: Mechano-insensitive nociceptors encode pain evoked by tonic pressure to human skin. Neuroscience 2000, 98: 793–800. 10.1016/S0306-4522(00)00189-5PubMedCrossRef

61.

Chae YJ, Zhang J, Au P, Sabbadini M, Xie GX, Yost CS: Discrete Change in Volatile Anesthetic Sensitivity in Mice with Inactivated Tandem Pore Potassium Ion Channel TRESK. Anesthesiology 2010, in press.

62.

Czirják G, Tóth ZE, Enyedi P: The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J Biol Chem 2004, 279: 18550–18558. 10.1074/jbc.M312229200PubMedCrossRef

63.

Lavoratore SR, Navarro OM, Grunebaum E, Ali M, Koo A, Schechter T, Gassas A, Doyle JJ, Lee Dupuis L: Cyclosporine-Induced Pain Syndrome in a Child Undergoing Hematopoietic Stem Cell Transplant. Annals of Pharmacotherapy 2009, 43: 767–771. 10.1345/aph.1L641PubMedCrossRef

64.

Collini A, De Bartolomeis C, Barni R, Ruggieri G, Bernini M, Carmellini M: Calcineurin-inhibitor induced pain syndrome after organ transplantation. Kidney international 2006, 70: 1367–1370. 10.1038/sj.ki.5001833PubMedCrossRef

65.

Niemann CU, Stabernack C, Serkova N, Jacobsen W, Christians U, Eger EI: Cyclosporine can increase isoflurane MAC. Anesth Analg 2002, 95: 930–934. table of contentsPubMed

66.

Wall PD, Devor M, Inbal R, Scadding JW, Schonfeld D, Seltzer Z, Tomkiewicz MM: Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 1979, 7: 103–111. 10.1016/0304-3959(79)90002-2PubMedCrossRef

67.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63. 10.1016/0165-0270(94)90144-9PubMedCrossRef

68.

Serra J, Campero M, Ochoa J, Bostock H: Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin. J Physiol 1999,515(Pt 3):799–811.PubMedCentralPubMedCrossRef

69.

Campero M, Serra J, Bostock H, Ochoa JL: Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 2001, 535: 855–865. 10.1111/j.1469-7793.2001.t01-1-00855.xPubMedCentralPubMedCrossRef

70.

Campero M, Serra J, Bostock H, Ochoa JL: Partial reversal of conduction slowing during repetitive stimulation of single sympathetic efferents in human skin. Acta Physiol Scand 2004, 182: 305–311. 10.1111/j.1365-201X.2004.01357.xPubMedCrossRef

71.

Weidner C, Schmidt R, Schmelz M, Hilliges M, Handwerker HO, Torebjork HE: Time course of post-excitatory effects separates afferent human C fibre classes. J Physiol 2000,527(Pt 1):185–191.PubMedCentralPubMedCrossRef

Title: TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury
Authors: Astrid Tulleuda
Barbara Cokic
Gerard Callejo
Barbara Saiani
Jordi Serra
Xavier Gasull
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-7-30

At a glance: The STEP trials

Springer Medicine

TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

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