期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 28, 期 1, 页码 12-19出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1460-9568.2008.06308.x
关键词
GDNF; IB4; pain; sensory neurons; versican
资金
- NINDS NIH HHS [R01 NS053880, R01 NS053880-03] Funding Source: Medline
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 GFR alpha 1/Ret: PLC gamma, 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.
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