Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors.
Neurons classified as nociceptors are dependent on nerve growth factor (NGF) during embryonic development, but a large subpopulation lose this dependence during embryonic and postnatal times and become responsive to the transforming growth factor beta family member, glial cell line-derived growth factor (GDNF). To elucidate the functional properties of GDNF-dependent nociceptors and distinguish them from nociceptors that retain NGF dependence, the cellular and physiologic properties of sensory neurons of wild-type and transgenic mice that overexpress GDNF in the skin (GDNF-OE) were analyzed using a skin, nerve, dorsal root ganglion, and spinal cord preparation, immunolabeling, and reverse transcriptase-PCR assays. Although an increase in peripheral conduction velocity of C-fibers in GDNF-OE mice was measured, other electrophysiological properties, including resting membrane potential and somal action potentials, were unchanged. We also show that isolectin B4 (IB4)-positive neurons, many of which are responsive to GDNF, exhibited significantly lower thresholds to mechanical stimulation relative to wild-type neurons. However, no change was observed in heat thresholds for the same population of cells. The increase in mechanical sensitivity was found to correlate with significant increases in acid-sensing ion channels 2A and 2B and transient receptor potential channel A1, which are thought to contribute to detection of mechanical stimuli. These data indicate that enhanced expression of GDNF in the skin can change mechanical sensitivity of IB4-positive nociceptive afferents and that this may occur through enhanced expression of specific types of channel proteins.
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Kathryn M
KM
Albers
C Jeffrey
CJ
Woodbury
Amy M
AM
Ritter
Brian M
BM
Davis
H Richard
HR
Koerber
D062565:Acid Sensing Ion Channels; D000200:Action Potentials; D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics; D004817:Epidermis / Q000294:innervation*; D005260:Female; D005727:Ganglia, Spinal / Q000502:physiology; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006358:Hot Temperature; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009475:Neurons, Afferent / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D009619:Nociceptors / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation; D011401:Promoter Regions, Genetic; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics; D013314:Stress, Mechanical; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics
C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D015220:Calcium Channels; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053547:Keratin-14; C507446:Krt14 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C485717:Trpv2 protein, mouse; C486760:Trpv3 protein, mouse; C486576:Trpv4 protein, mouse; D007633:Keratins