title: TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury.
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.
authors.affiliation: Neurophysiology Lab, Dept, Physiological Sciences I, Medical School, University of Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Astrid
authors.initials: A
authors.lastname: Tulleuda
authors.forename: Barbara
authors.initials: B
authors.lastname: Cokic
authors.forename: Gerard
authors.initials: G
authors.lastname: Callejo
authors.forename: Barbara
authors.initials: B
authors.lastname: Saiani
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra
authors.forename: Xavier
authors.initials: X
authors.lastname: Gasull
mesh_terms: D000818:Animals; D019771:Axotomy; D002478:Cells, Cultured; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009437:Neuralgia / Q000209:etiology*; D009619:Nociceptors / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries*
chemical_list: D015221:Potassium Channels; C476574:KCNK18 protein, human; C546314:Kcnk18 protein, rat; C503433:Kcnk4 protein, mouse; C486498:Kcnk18 protein, mouse