Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways.
Many sensations of pain are evoked by mechanical stimuli, and in inflammatory conditions, sensitivity to such stimuli is commonly increased. Here we used cultured sensory neurons as a model of the peripheral terminal to investigate the effects of inflammatory signaling pathways on mechanosensitive ion channels. Activation of two of these pathways enhanced transduction in a major population of nociceptors. The proinflammatory neurotrophin nerve growth factor caused an up-regulation of mechanically activated currents via a transcriptional mechanism. Activators of PKC, given in vitro and in vivo, also caused an increase in mechanically activated membrane current and behavioral sensitization to mechanical stimulation, respectively. The effect of activating PKC was inhibited by tetanus toxin, suggesting that insertion of new channels into the cell membrane is involved in sensitization. These results reveal previously undescribed mechanisms by which PKC and nerve growth factor synergistically enhance the response of nociceptors to mechanical stimuli, suggesting possible targets for pain treatment.
Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello, via del Fosso di Fiorano 64, 00143 Rome, Italy.
Amalia
A
Di Castro
Liam J
LJ
Drew
John N
JN
Wood
Paolo
P
Cesare
D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D040542:Mechanotransduction, Cellular; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013744:Tetanus Toxin / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D013744:Tetanus Toxin; D020932:Nerve Growth Factor; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate