Abstract
We have analyzed signaling pathways involved in neurotrophic factor (NTF)-induced upregulation of nociceptive properties, specifically vanilloid receptor type 1 (VR1), by adult rat dorsal root ganglion neurons. Upregulation of VR1 by nerve growth factor and glial cell line-derived neurotrophic factor is partially blocked by a MEK inhibitor. Dominant negative Ras, but not Rap, blocks NTF-induced ERK activation and VR1 upregulation. Activated Ras mimics NTF-mediated induction of VR1 in dorsal root ganglion neurons. An inhibitor of phosphatidylinositol 3-kinase, LY294002, also inhibited NTF-induced VR1 upregulation. However, this may at least in part be due to a block of NTF-induced ERK activation. Constitutive simultaneous stimulation of both ERK and phosphatidylinositol 3-kinase is not sufficient for VR1 upregulation. Together, the data suggest that VR1 expression by dorsal root ganglion neurons is regulated by common Ras-dependent pathways.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Capsaicin / pharmacology
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / drug effects
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Cyclic AMP Response Element-Binding Protein / metabolism
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Enzyme Inhibitors / pharmacology
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Ganglia, Spinal / cytology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism*
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Glial Cell Line-Derived Neurotrophic Factor
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Growth Factor / metabolism
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Nerve Growth Factor / pharmacology
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Nerve Growth Factors / metabolism*
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Nerve Growth Factors / pharmacology
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Neurons, Afferent / cytology
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Neurons, Afferent / drug effects
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Neurons, Afferent / metabolism*
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Nociceptors / cytology
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Nociceptors / drug effects
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Nociceptors / metabolism*
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Pain / metabolism
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Pain / physiopathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptors, Drug / drug effects
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Receptors, Drug / metabolism*
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Up-Regulation / drug effects
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Up-Regulation / physiology*
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ras Proteins / metabolism*
Substances
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Gdnf protein, rat
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Glial Cell Line-Derived Neurotrophic Factor
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Nerve Growth Factors
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Drug
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Nerve Growth Factor
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Mitogen-Activated Protein Kinases
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ras Proteins
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Capsaicin