Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain.
Glial cell line-derived neurotrophic factor (GDNF) is necessary for the development of sensory neurons, and appears to be critical for the survival of dorsal root ganglion (DRG) cells that bind the lectin IB4. Intrathecal infusion of GDNF has been shown to prevent and reverse the behavioral expression of experimental neuropathic pain arising from injury to spinal nerves. This effect of GDNF has been attributed to a blockade of the expression of the voltage gated, tetrodotoxin-sensitive sodium channel subtype, Na(V)1.3, in the injured DRG. Here we report that GDNF given intrathecally via osmotic-pump to nerve-injured rats (L5/L6 spinal nerve ligation) prevented the changes in a variety of neurochemical markers in the DRG upon injury. They include a loss of binding of IB4, downregulation of the purinergic receptor P2X(3), upregulation of galanin and neuropeptide Y immunoreactivity in large diameter DRG cells, and expression of the transcription factor ATF3. GDNF infusion concomitantly prevented the development of spinal nerve ligation-induced tactile hypersensitivity and thermal hyperalgesia. These observations suggest that high dose, exogenous GDNF has a broad neuroprotective role in injured primary afferent. The receptor(s) that mediates these effects of GDNF is not known. GDNF's ability to block neuropathic pain states is not likely to be specific to Na(V)1.3 expression.
Department of Pharmacology, University of Arizona, Tucson 85724, USA.
R
R
Wang
W
W
Guo
M H
MH
Ossipov
T W
TW
Vanderah
F
F
Porreca
J
J
Lai
D051696:Activating Transcription Factors; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D007839:Functional Laterality; D019004:Galanin / Q000378:metabolism; D005727:Ganglia, Spinal / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007150:Immunohistochemistry; D037102:Lectins / Q000378:metabolism; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D051696:Activating Transcription Factors; D001798:Blood Proteins; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D037102:Lectins; D009414:Nerve Growth Factors; D009478:Neuropeptide Y; C546407:P2RX3 protein, human; C546410:P2rx3 protein, rat; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D014157:Transcription Factors; D019004:Galanin