Abstract
The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4-saporin, a selective toxin for IB4+/Ret+-nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFRa1/Ret: PLCc, CDK5, PI3K,MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype.
MeSH terms
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ADAM Proteins / metabolism
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ADAMTS4 Protein
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Animals
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Cyclin-Dependent Kinase 5 / metabolism*
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Electrophysiology
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Enzyme Inhibitors / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Glial Cell Line-Derived Neurotrophic Factor / pharmacology
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Glycoproteins / metabolism
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Hyperalgesia / chemically induced
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Hyperalgesia / metabolism*
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Lectins / metabolism
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Male
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Mitogen-Activated Protein Kinases / metabolism*
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Nerve Growth Factor / pharmacology
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / metabolism
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Pain Measurement
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Phosphatidylinositol 3-Kinases / metabolism*
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Phospholipase C gamma / metabolism*
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Procollagen N-Endopeptidase / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / physiology*
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Versicans / genetics
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Versicans / metabolism*
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src-Family Kinases / metabolism*
Substances
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Enzyme Inhibitors
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Glial Cell Line-Derived Neurotrophic Factor
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Glycoproteins
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Lectins
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Oligonucleotides, Antisense
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Vcan protein, rat
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Versicans
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Nerve Growth Factor
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src-Family Kinases
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Cyclin-Dependent Kinase 5
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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Phospholipase C gamma
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ADAM Proteins
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Procollagen N-Endopeptidase
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ADAMTS4 Protein