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Comparative Study
. 2005 May 11;25(19):4868-78.
doi: 10.1523/JNEUROSCI.0249-05.2005.

trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors

Xin Fang  1 , Laiche Djouhri, Simon McMullan, Carol Berry, Kenji Okuse, Stephen G Waxman, Sally N Lawson
Affiliations
Comparative Study

trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors

Xin Fang et al. J Neurosci. .

Abstract

To test the hypothesis that trkA (the high-affinity NGF receptor) is selectively expressed in nociceptive dorsal root ganglion (DRG) neurons, we examined the intensity of trkA immunoreactivity in single dye-injected rat DRG neurons, the sensory receptor properties of which were identified in vivo with mechanical and thermal stimuli. We provide the first evidence in single identified neurons that strong trkA expression in DRGs is restricted to nociceptive neurons, probably accounting for the profound influence of NGF on these neurons. Furthermore, we demonstrate that trkA expression is as high in rapidly conducting (Aalpha/beta) as in more slowly conducting (Adelta and C) nociceptors. All Aalpha/beta low-threshold mechanoreceptors (LTMs) are trkA negative, although weak but detectable trkA is present in some C and Adelta LTMs. NGF can influence electrophysiological properties of DRG neurons, probably by binding to trkA. We found positive correlations for single identified Aalpha/beta (but not C or Adelta) nociceptors between trkA immunocytochemical intensity and electrophysiological properties typical of nociceptors, namely long action potential and afterhyperpolarization durations and large action potential amplitudes. Furthermore, for Aalpha/beta (notCorAdelta) nociceptors, trkA intensity is inversely correlated with conduction velocity. Similar relationships, again only in Aalpha/beta nociceptors, between electrophysiological properties and trkA expression exist for sodium channel Nav1.8 but not Nav1.9 immunoreactivities. These findings suggest that in Aalpha/beta nociceptors, influences of NGF on expression levels of Nav1.8 are related to, and perhaps limited by, expression levels of trkA. This view is supported by a positive correlation between immuno-intensities of trkA and Nav1.8 in A-fiber, but not C-fiber, nociceptors.

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Figures

Figure 1.
Figure 1.
A, B, Sizes of all non-dye-injected neuronal profiles with nuclei in sections of one L5 DRG from each of three rats (A) compared with those of identified dye-injected neurons (B). Vertical dotted lines indicate boundaries between small, medium, and large neurons. Horizontal dotted lines indicate borderlines between negative and positive neurons and between weakly positive (20-40%) and strongly positive (≥40%) neurons. C, trkA intensities of physiologically identified DRG neurons; a Kruskal-Wallis test comparing medians of the three groups of nociceptors shows a significant difference between Aδ and Aα/β neurons and no differences between the four groups of Aα/β LTMs; Mann-Whitney U tests show significant differences between Aδ nociceptors and Aδ LTM neurons, between Aα/β nociceptors and LTMs, and between Aδ and all Aα/β LTMs. CLTM neurons are excluded, because n = 3. D, trkA intensity in CLTMs and populations of C nociceptive neurons. E, Comparisons of trkA intensities of Aα/β-fiber HTM subgroups. Moderate pressure (MP) units had significantly lower trkA intensities than other HTMs with superficial or deeper (dermal and subcutaneous together) receptive fields, and HTMs with superficial receptive fields had significantly lower intensities than units with deep receptive fields (Mann-Whitney tests). F, Photomicrographs show fluorescent images of representative dye-injected neurons in insets to left: dyes were Lucifer yellow, cascade blue, and for the two lowest cells ethidium bromide; note the typically nuclear fluorescence with cascade blue and Lucifer yellow. The same neurons stained for trkA, under interference contrast optics, are indicated by arrows (right). Asterisks indicate examples of trkA- neurons. The top three injected neurons are strongly trkA+, and the last is a trkA-MP unit. The scale bar (50 μm; top left image) applies to all photomicrographs, including insets. For C and E, *p < 0.05, **p < 0.01, ***p < 0.001. NOC, Nociceptive; UNR, C-fiber unresponsive; SA, slowly adapting; F/G, field or guard hair; RA, rapidly adapting; MS, muscle spindle; MC, mechano-cold; PM, polymodal; MH, mechano-heat. Depth in tissues: Sup, superficial; Derm, dermal; Sub, subcutaneous.
Figure 2.
Figure 2.
trkA intensity plotted against dorsal root CVs for all C-fiber (A) and all A-fiber neurons (B) and comparison of CVs in subgroups of Aα/β moderate pressure (MP) units with other Aα/β HTMs with receptive fields at different tissue depths (C). In B, p and r2 values for regression lines for all A-fiber nociceptors, for all A-fiber LTMs, and Aα/β nociceptors are specified in Results. The vertical dotted line in B indicates the upper border of CV for Aδ fibers (6.5 m/s). In A and B, the horizontal dotted line indicates the 20% borderline between trkA+ and trkA-. In C, MP units had significantly faster CVs than other Aα/β HTMs with superficial or deeper (dermal and subcutaneous together) receptive fields, and Aα/β HTMs with superficial receptive fields had lower CVs than those with deep receptive fields (Mann-Whitney tests; *p < 0.05; **p < 0.01). NOC, Nociceptive; Sup, superficial; Derm, dermal; Sub, subcutaneous. Symbols and abbreviations are as in Figure 1.
Figure 3.
Figure 3.
Intensity of trkA, Nav1.8, and Nav1.9 immunostaining versus AP duration and height. A, AP duration in all neurons subdivided into C, Aδ, and Aα/β. B, AP duration in Aα/β neurons. C, AP height in Aα/β neurons. Units in B and C are subdivided into nociceptive and LTM units. A-fiber unresponsive neurons are excluded. In A and B, only neurons with resting membrane potential greater than or equal to -40 mV (with 1 exception: -39 mV in 1 C nociceptor) and overshooting somatic APs are included. In C, all Aα/β neurons with AP overshoot more than or equal to -20 mV and AP height ≥35 mV are included. Symbols in B relate to B and C. Regression lines are given for significant linear correlation, and p and r2 values are given in Table 1. NOC, Nociceptive.
Figure 4.
Figure 4.
trkA intensity versus Nav1.8 (left) or Nav1.9 (right) intensity in different sections from the same identified neurons. A-fiber unresponsive neurons are excluded. Left, A linear correlation between trkA intensity and Nav1.8 intensity exists in all Aα/β units (p < 0.0001; r2 = 0.36); Aα/β nociceptors (p < 0.005; r2 = 0.29); all Aδ units (p < 0.005; r2 = 0.48); Aδ nociceptors (p < 0.005; r2 = 0.38). No such correlation is in C-fiber units (p > 0.05). Right, There is a linear correlation between trkA intensity and Nav1.9 intensity only in all Aα/β units (p < 0.005; r2 = 0.17). The vertical and horizontal dotted lines from y-axis and from x-axis indicate the borderlines between positive and negative for trkA and for Nav1.8 or Nav1.9, respectively. NOC, Nociceptive; C UNR, C-fiber unresponsive. For p, n, and r2 values, see Results.
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