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@ARTICLE{Funk:238,
      author       = {Funk, K. and Woitecki, A. and Franjic-Würtz, C. and
                      Gensch, T. and Möhrlen, F. and Frings, S.},
      title        = {{M}odulation of chloride homeostasis by inflammatory
                      mediators in dorsal root ganglion neurons},
      journal      = {Molecular pain},
      volume       = {4},
      issn         = {1744-8069},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {PreJuSER-238},
      pages        = {32 - 43},
      year         = {2008},
      note         = {This work was supported by the Deutsche
                      Forschungsgemeinschaft (Fr 937/6).},
      abstract     = {Chloride currents in peripheral nociceptive neurons have
                      been implicated in the generation of afferent nociceptive
                      signals, as Cl- accumulation in sensory endings establishes
                      the driving force for depolarizing, and even excitatory, Cl-
                      currents. The intracellular Cl- concentration can, however,
                      vary considerably between individual DRG neurons. This
                      raises the question, whether the contribution of Cl-
                      currents to signal generation differs between individual
                      afferent neurons, and whether the specific Cl- levels in
                      these neurons are subject to modulation. Based on the
                      hypothesis that modulation of the peripheral Cl- homeostasis
                      is involved in the generation of inflammatory hyperalgesia,
                      we examined the effects of inflammatory mediators on
                      intracellular Cl- concentrations and on the expression
                      levels of Cl- transporters in rat DRG neurons.We developed
                      an in vitro assay for testing how inflammatory mediators
                      influence Cl- concentration and the expression of Cl-
                      transporters. Intact DRGs were treated with 100 ng/ml NGF,
                      1.8 microM ATP, 0.9 microM bradykinin, and 1.4 microM PGE2
                      for 1-3 hours. Two-photon fluorescence lifetime imaging with
                      the Cl--sensitive dye MQAE revealed an increase of the
                      intracellular Cl- concentration within 2 hours of treatment.
                      This effect coincided with enhanced phosphorylation of the
                      Na+-K+-2Cl- cotransporter NKCC1, suggesting that an
                      increased activity of that transporter caused the early rise
                      of intracellular Cl- levels. Immunohistochemistry of NKCC1
                      and KCC2, the main neuronal Cl- importer and exporter,
                      respectively, exposed an inverse regulation by the
                      inflammatory mediators. While the NKCC1 immunosignal
                      increased, that of KCC2 declined after 3 hours of treatment.
                      In contrast, the mRNA levels of the two transporters did not
                      change markedly during this time. These data demonstrate a
                      fundamental transition in Cl- homeostasis toward a state of
                      augmented Cl- accumulation, which is induced by a 1-3 hour
                      treatment with inflammatory mediators.Our findings indicate
                      that inflammatory mediators impact on Cl- homeostasis in DRG
                      neurons. Inflammatory mediators raise intracellular Cl-
                      levels and, hence, the driving force for depolarizing Cl-
                      efflux. These findings corroborate current concepts for the
                      role of Cl- regulation in the generation of inflammatory
                      hyperalgesia and allodynia. As the intracellular Cl-
                      concentration rises in DRG neurons, afferent signals can be
                      boosted by excitatory Cl- currents in the presynaptic
                      terminals. Moreover, excitatory Cl- currents in peripheral
                      sensory endings may also contribute to the generation or
                      modulation of afferent signals, especially in inflamed
                      tissue.},
      keywords     = {Adenosine Triphosphate: pharmacology / Animals /
                      Bradykinin: pharmacology / Chlorides: metabolism /
                      Dinoprostone: pharmacology / Ganglia, Spinal: cytology /
                      Ganglia, Spinal: drug effects / Ganglia, Spinal: metabolism
                      / Homeostasis: drug effects / Homeostasis: physiology /
                      Inflammation Mediators: pharmacology / Nerve Growth Factors:
                      pharmacology / Neurons: drug effects / Neurons: metabolism /
                      Organ Culture Techniques / Rats / Chlorides (NLM Chemicals)
                      / Inflammation Mediators (NLM Chemicals) / Nerve Growth
                      Factors (NLM Chemicals) / Dinoprostone (NLM Chemicals) /
                      Adenosine Triphosphate (NLM Chemicals) / Bradykinin (NLM
                      Chemicals) / J (WoSType)},
      cin          = {INB-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)VDB804},
      pnm          = {Funktion und Dysfunktion des Nervensystems},
      pid          = {G:(DE-Juel1)FUEK409},
      shelfmark    = {Neurosciences},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:18700020},
      pmc          = {pmc:PMC2526990},
      UT           = {WOS:000258959400001},
      doi          = {10.1186/1744-8069-4-32},
      url          = {https://juser.fz-juelich.de/record/238},
}