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000000238 084__ $$2WoS$$aNeurosciences
000000238 1001_ $$0P:(DE-HGF)0$$aFunk, K.$$b0
000000238 245__ $$aModulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons
000000238 260__ $$aLondon$$bBioMed Central$$c2008
000000238 300__ $$a32 - 43
000000238 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000000238 440_0 $$019121$$aMolecular Pain$$v4$$x1744-8069
000000238 500__ $$aThis work was supported by the Deutsche Forschungsgemeinschaft (Fr 937/6).
000000238 520__ $$aChloride 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.
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000000238 650_2 $$2MeSH$$aAdenosine Triphosphate: pharmacology
000000238 650_2 $$2MeSH$$aAnimals
000000238 650_2 $$2MeSH$$aBradykinin: pharmacology
000000238 650_2 $$2MeSH$$aChlorides: metabolism
000000238 650_2 $$2MeSH$$aDinoprostone: pharmacology
000000238 650_2 $$2MeSH$$aGanglia, Spinal: cytology
000000238 650_2 $$2MeSH$$aGanglia, Spinal: drug effects
000000238 650_2 $$2MeSH$$aGanglia, Spinal: metabolism
000000238 650_2 $$2MeSH$$aHomeostasis: drug effects
000000238 650_2 $$2MeSH$$aHomeostasis: physiology
000000238 650_2 $$2MeSH$$aInflammation Mediators: pharmacology
000000238 650_2 $$2MeSH$$aNerve Growth Factors: pharmacology
000000238 650_2 $$2MeSH$$aNeurons: drug effects
000000238 650_2 $$2MeSH$$aNeurons: metabolism
000000238 650_2 $$2MeSH$$aOrgan Culture Techniques
000000238 650_2 $$2MeSH$$aRats
000000238 650_7 $$00$$2NLM Chemicals$$aChlorides
000000238 650_7 $$00$$2NLM Chemicals$$aInflammation Mediators
000000238 650_7 $$00$$2NLM Chemicals$$aNerve Growth Factors
000000238 650_7 $$0363-24-6$$2NLM Chemicals$$aDinoprostone
000000238 650_7 $$056-65-5$$2NLM Chemicals$$aAdenosine Triphosphate
000000238 650_7 $$058-82-2$$2NLM Chemicals$$aBradykinin
000000238 650_7 $$2WoSType$$aJ
000000238 7001_ $$0P:(DE-HGF)0$$aWoitecki, A.$$b1
000000238 7001_ $$0P:(DE-HGF)0$$aFranjic-Würtz, C.$$b2
000000238 7001_ $$0P:(DE-Juel1)131924$$aGensch, T.$$b3$$uFZJ
000000238 7001_ $$0P:(DE-HGF)0$$aMöhrlen, F.$$b4
000000238 7001_ $$0P:(DE-HGF)0$$aFrings, S.$$b5
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000000238 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526990
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000000238 9201_ $$0I:(DE-Juel1)VDB804$$d31.12.2008$$gINB$$kINB-1$$lZelluläre Biophysik$$x0
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