GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican.

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.
Authors	Oliver Bogen, Elizabeth K Joseph, Xiaojie Chen, Jon D Levine
Journal	The European journal of neuroscience (Eur J Neurosci) Vol. 28 Issue 1 Pg. 12-9 (Jul 2008) ISSN: 1460-9568 [Electronic] France
PMID	18616564 (Publication Type: Journal Article)
Chemical References	Enzyme Inhibitors Glial Cell Line-Derived Neurotrophic Factor Glycoproteins Lectins Oligonucleotides, Antisense Vcan protein, rat Versicans Nerve Growth Factor src-Family Kinases Cyclin-Dependent Kinase 5 Extracellular Signal-Regulated MAP Kinases Mitogen-Activated Protein Kinases Phospholipase C gamma ADAM Proteins Procollagen N-Endopeptidase ADAMTS4 Protein
Topics	ADAM Proteins (metabolism) ADAMTS4 Protein Animals Cyclin-Dependent Kinase 5 (metabolism) Electrophysiology Enzyme Inhibitors (metabolism) Extracellular Signal-Regulated MAP Kinases (metabolism) Glial Cell Line-Derived Neurotrophic Factor (pharmacology) Glycoproteins (metabolism) Hyperalgesia (chemically induced, metabolism) Lectins (metabolism) Male Mitogen-Activated Protein Kinases (metabolism) Nerve Growth Factor (pharmacology) Oligonucleotides, Antisense (genetics, metabolism) Pain Measurement Phosphatidylinositol 3-Kinases (metabolism) Phospholipase C gamma (metabolism) Procollagen N-Endopeptidase (metabolism) Rats Rats, Sprague-Dawley Signal Transduction (physiology) Versicans (genetics, metabolism) src-Family Kinases (metabolism)

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