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. 2006 Mar 15;26(11):2981-90.
doi: 10.1523/JNEUROSCI.4863-05.2006.

Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors

Kathryn M Albers  1 , C Jeffrey Woodbury, Amy M Ritter, Brian M Davis, H Richard Koerber
Affiliations

Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors

Kathryn M Albers et al. J Neurosci. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Examples of intracellular recording and immunostaining of cutaneous C-fiber somata in WT mice. a, Somal action potential and first derivative from a C-polymodal nociceptor. b, The cell in a stained positively for IB4 (red) and P2X3 (blue). c, Somal action potential and first derivative of a C-mechanonociceptor. d, This cell was IB4 negative (red) and CGRP positive (blue).
Figure 2.
Figure 2.
Examples of two C-fiber somata recorded from and labeled in a WT preparation. a, The broad inflected somal action potential and first derivative from a cell characterized as a C-polymodal nociceptor. b, The sensory neuron in a stained with NB (red) was found to be IB4 (green) positive and CGRP (blue) negative. Overlap of triple labeling is shown in the bottom right panel. c, This neuron was characterized as a CLTM that also responded to cooling of the skin. It had a relatively brief inflected somal action potential. d, The NB-labeled cell shown in c was negative for IB4 (green) and CGRP (blue). e, Examples of the mechanical and heat responses of a C-polymodal nociceptor that was IB4 positive and CGRP negative. f, Example of the mechanical and thermal response properties of a CLTMR that was negative for IB4 and CGRP. Note that these fibers exhibited after discharge after the heat stimulus.
Figure 3.
Figure 3.
Example of the most commonly observed C-fiber comprehensive phenotype in the GDNF-OE preparations. a, This sensory neuron had a broad inflected somal action potential and was characterized as a low-threshold mechanoreceptor by its vigorous response to a very small force applied using a calibrated (0.07 mN) von Frey filament. It also responded vigorously to noxious heating of the skin, which is characteristic of a heat nociceptor. b, Neuron characterized in a was IB4 (red) and P2X3 (blue) positive. The bottom panel shows triple-label overlap. c, Dorsal horn termination of C-fiber shown in a and b. Dotted lines show the outline of the dorsal horn and the boundary between laminas II and III. d, High-power view to show fiber arborization in laminas I–II outer. Note that this fiber exhibited after discharge after the heat stimulus.
Figure 4.
Figure 4.
Example of a second C-fiber recorded from a GDNF-OE that shows a similar phenotype to the afferent shown in Figure 1. a, This NB-labeled cell (green) stained positively for IB4 (red) but was negative for CGRP (blue). b, Fiber shown in a also projected into laminas I and II outer and exhibited extensive arborization c.
Figure 5.
Figure 5.
Summary of physiological data. a, Cumulative sum plot showing a significant decrease in mechanical threshold of C-fibers in GDNF-OE mice (n = 34) compared with WT mice (n = 31). b, Bar graph depicting the significant increase (*p < 0.01, χ2 test) in the number of C-fibers responding to heating of the skin in GDNF-OE mice (n = 36) compared with WT mice (n = 31). More than 97% of C-fibers in transgenic DRG responded to heat compared with 81% in WT mice. c, Scatter plot showing the relationship between heat sensitivity and mechanical threshold for C-fibers in WT and GDNF-OE mice. d, Scatter plot showing the relationship between somal action potential duration (at half-amplitude) and mechanical threshold.
Figure 6.
Figure 6.
Increased immunostaining of ASIC2 was found in IB4-positive neurons of GDNF-OE mice. a, In WT ganglia, strong ASIC2 labeling is seen in large neurons (asterisk) compared with weak labeling in smaller neurons (arrow). b, Many of the smaller weakly ASIC2-labeled neurons were IB4 positive (arrow). c, Overlap of ASIC2/IB4 labeling in WT ganglia (arrow). d, In transgenic ganglia, ASIC2 labeling intensity was substantially increased and overlapped with IB4 reactivity (arrow). Some small IB4-negative cells were also labeled (arrowhead). e, Note the GDNF-induced hypertrophy of IB4 neurons in transgenic ganglia (Zwick et al., 2002). f, Overlap of ASIC2 and IB4 labeling in GDNF-OE ganglia. ASIC2 immunostaining in WT (g) and GDNF-OE (h) dorsal cutaneous nerves. Note the overall increase in labeling intensity in GDNF-OE nerve.
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