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Adrenergic beta-Agonists/pharmacology
Analysis of Variance
Animals
Calcium/*metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
Cells, Cultured
Cyclic AMP/analogs & derivatives/pharmacology
Electric Stimulation
Enzyme Inhibitors/pharmacology
Ganglia, Spinal/cytology
Hyperalgesia/drug therapy/physiopathology
Inositol 1,4,5-Trisphosphate/pharmacology
Isoproterenol/pharmacology
Male
Nerve Fibers/drug effects/physiology
Neurons/drug effects/*metabolism
Nociceptors/*physiology
Pain Threshold/drug effects/*physiology
Protein Kinase C-epsilon/metabolism
Protein Transport/drug effects
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled/metabolism
Ryanodine/pharmacology
Signal Transduction/drug effects/physiology
TRPV Cation Channels/metabolism
Thionucleotides/pharmacology
Uridine Triphosphate/pharmacology
Abstract:
Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCepsilon) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCepsilon signaling pathway resulted in PKCepsilon translocation. We identified a novel inhibitory cascade to branch off upstream of PKCepsilon, but downstream of Epac via IP3-induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second 'sensitizing' stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII-dependent manner. This mechanism was also observed by in vivo C-fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.
