GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican.
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.
Bogen
Oliver
O
Division of Neuroscience, Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0440, USA.
Joseph
Elizabeth K
EK
Chen
Xiaojie
X
Levine
Jon D
JD
D051722:ADAM Proteins / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D053675:Versicans / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D051360:Cyclin-Dependent Kinase 5; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; D037102:Lectins; D020928:Mitogen-Activated Protein Kinases; D020932:Nerve Growth Factor; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D011348:Procollagen N-Endopeptidase; D053675:Versicans; D019061:src-Family Kinases; C508324:Vcan protein, rat