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Review
. 2019 Oct;11:125-146.
doi: 10.1016/j.cophys.2019.10.005.

Nociceptor Subtypes and Their Incidence in Rat Lumbar Dorsal Root Ganglia (DRGs): Focussing on C-polymodal Nociceptors, Aβ-nociceptors, Moderate Pressure Receptors and Their Receptive Field Depths

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Review

Nociceptor Subtypes and Their Incidence in Rat Lumbar Dorsal Root Ganglia (DRGs): Focussing on C-polymodal Nociceptors, Aβ-nociceptors, Moderate Pressure Receptors and Their Receptive Field Depths

Sally N Lawson et al. Curr Opin Physiol. .
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Abstract

A recent study with Ca++-sensitive-dyes in neurons in whole DRGs (Table 5) found that much lower percentages of nociceptors were polymodal-nociceptors (PMNs) (Emery et al., 2016), than the 50-80% values in many electrophysiological fiber studies. This conflict highlighted the lack of knowledge about percentages of nociceptor-subtypes in the DRG. This was analysed from intracellularly-recorded neurons in rat lumbar DRGs stimulated from outside the skin. Polymodal nociceptors (PMNs) were 11% of all neurons and 19% of all nociceptors. Most PMNs had C-fibers (CPMNs). Percentages of C-nociceptors that were CPMNs varied with receptive field (RF) depths, whether superficial (∼80%), dermal (25%), deep (0%) or cutaneous (superficial + dermal) (40%). This explains CPMN percentages 40-90%, being highest, in electrophysiological studies using cutaneous nerves, and lowest in studies that also include deep RFs, including ours, and the recent Ca++-imaging studies in whole DRGs. Despite having been originally described in 1967 (Burgess and Perl), both Aβ-nociceptors and Aβ-moderate pressure receptors (MPRs) remain overlooked. Most A-fiber nociceptors in rodents have Aβ-fibers. Of rat lumbar Aβ-nociceptors with superficial RFs, 50% were MPRs with variable medium-low trkA-expression. Despite having conduction velocities at the two extremes for nociceptors, both CPMNs and MPRs have relatively low thresholds, superficial/epidermal RFs and low trkA-expression. For abbreviations used see Table 5.

Figures

Figure 1
Figure 1
(a) CVs of nociceptive and LTMR L4/L5 DRG neurons. Because of the difficulty of showing distributions of C-fiber and A-fiber CVs on the same graph, log10 CVs were plotted with bin widths of 0.1 log units; unlogged CVs shown at top of graph. All nociceptors are red; and C-LTMRs and Aαβ-LTMRs (low threshold mechanoreceptors) are blue, and Aδ-LTMRs (D hair units) are green for. Vertical lines and arrows show boundaries between CV groups, determined by compound action potential recordings by X Fang 2002 [17], and confirmed by CV distributions of Aαβ-LTMRs and Aδ-LTMRs (a and b). (b) Data in (a) adjusted to counter bias during recordings. Adjustments (Table 1 legend) to compensate for rejection of Aαβ-LTMRs during recording, and to adjust for the underestimated C-neuron population to make up 70% of the total [30], using values shown on graph and Table 1. (c) The two overlapping size distribution of NF-rich and NF-poor rat L4-L6 DRG neurons: Size = area = cross-sectional area measured at nuclear, mid-soma, level. NF-poor neurons (open histogram) have C-fibers [21,22]. This population includes mainly nociceptors and unidentified units, including silent-nociceptors, with few LTMRs in these DRGs that project mainly to distal hindlimb. The neurofilament-rich (NF-rich, striped histogram) neurons have A-fibers and are mainly LTMRs, with some nociceptors [21,22]. (d) Cartoon of area distributions of C, Aδ- and Aαβ-neuronal somata. Means and ranges for each population from previously published plots [14,21,26], but amplitude of the C-neuron population (red) is adjusted upwards (adjustment 2, see Table 1 legend) to compensate for underrecording of C-neurons. The Aδ-neurons have medium-sized somata that overlap with C-neurons and Aα/β-neurons. It is not known whether the Aδ-neurons are underrepresented (indicated by two dotted outlines). (e) Percentages of C-, Aδ- and Aα/β-neurons that were nociceptive, LTM or unidentified/silent. Only Aαβ-percentages were adjusted (Table 1 legend). No C-neuron adjustment needed as comparisons are within CV groups. (f) Similar to E but subdivided into smaller CV groups to show the changes in these percentages. (g) Percentages of nociceptors with superficial RFs. CVs (log plot) of nociceptors with receptive fields (RFs) that are superficial (red), or in dermal or deeper tissues (pink). The percentage with superficial RFs is low (∼18%) in C-nociceptors, higher in Aδ-nociceptors and increases with CV in Aβ-nociceptors to dominate in the 12–20 m/s range. (h) Summary graph. Percentages of C, through Aδ and Aαβ-nociceptors with superficial, dermal or deep RFs are shown.
Figure 2
Figure 2
(a) Percentages of nociceptors with superficial RFs that are PMNs. This is high (79%) for C-nociceptors, decreasing through Aδ (average ∼14%) to almost none (∼3%) of Aαβ-nociceptors. (b) Percentage contribution of PMNs to all neurons. The vast majority of PMNs were C-nociceptors with superficial RFs. None with deep RFs and no A-nociceptors with dermal RFs showed responses to noxious heat. (c) IB4 relative immuno-intensities relative to C-nociceptor subtypes. This includes only units in this Bristol data set. It is a different plot of data most of which were previously published [26]. Here, the limits are defined more precisely, in that deep HTMRs and unresponsive units are included only if comprehensively tested with all types of noxious mechanical and noxious thermal stimuli, except for open symbols in CM deep that were not heat tested. The grey bands of 0–20% indicate negativity for IB4, 20–40% indicates weak staining, and 60–100% indicates strong staining. Note the gap in the CUnr (C-unresponsive) units between 40–70% suggesting two possible groups, strongly IB4+ and negative or weakly IB4+. Also note the IB4+ CMH and IB4 CMC units. Dermal and deep HTMRs were mostly negative to medium but not very strong IB4-immunointensities. (d) trkA versus IB4-immunointensities in C-Unresponsive neurons: All these neurons are from this Bristol database, and each had immunocytochemistry for trkA and IB4 carried out on different sections of the same neuron. (e–g) A-fiber HTMRs and MPRs. (e) Incidence of A-fiber HTMRs and MPRs with superficial RFs. For definitions see Sections: A-fiber PMNs and Moderate pressure receptors. MPRs are nociceptors that fire in response to moderate, non-noxious, pressure, but fire faster to higher intensity mechanical stimuli, encoding intensity through the noxious range [12••]. High threshold mechanoreceptors (HTMRs) are nociceptors with higher mechanical thresholds than MPRs that do not respond, or respond poorly, to moderate pressure. (f) MPRs as a percentage of A-nociceptors with superficial RFs. This increases with CV, being low (15%) in the Aδ-range, and rising to 49% in the Aαβ-range especially above 16 m/s (log 1.2) when the incidence is declining. NB All MPRs had superficial RFs. (g) Aβ-MPRs and HTMRs: trkA versus CV and RF depth. Redrawn from Fang et al. [9]. In Aαβ-nociceptors: MPRs have the fastest CVs and lowest trkA-expression. trkA-expression was highest in nociceptors with dermal or deep RFs, was next highest in nociceptors with superficial RFs and lowest in MPRs.
Figure 3
Figure 3
Pie charts of neuronal subtypes. Percentage contributions of CV groups and main neuronal types to the rat L4/L5 DRG. The top chart is all neurons, and below the C, Aδ and Aαβ charts are shown with their sizes approximately proportional to their contributions to the total population, and the percentage contributions of PMNs and MPRs to the DRGs. Arrows and percentages at C, Aδ and Aαβ-charts show contributions of PMN and MPR neurons to the total in that CV group.
Figure 4
Figure 4
Relationships between IB4, trkA, CV, mechanical nociceptor types, RF depths, and thresholds. Diagrammatic illustration relates features across the nociceptor CV range, but below 1 m/s no correlation of the information with CV is intended (section: CVs of C-nociceptor subtypes). The colour code relates to neuronal expressions of IB4+/MrgprD+ (blue), trkA+ (red) and IB4+/trkA+ (purple) neurons, and mRNA for trkC (orange) see sections: trkA and IB4/MrgprD expressing C-fiber neurons and Chemical phenotypes of A-fiber nociceptors. (a) Incidence of trkA+ or trkC-nociceptors relative to CV for A-fiber neurons. Summary boxes show some properties of trkA+ and IB4+/MrgprD+ nociceptors: receptors in bolds, ligands for receptors in italics. Arrows: ↑ upregulates, → causes, ↓ decreases. Beside channels are shown properties (lower case) that correlate with the channel expression (immunointensity). Strongly IB4+ C-neurons are more hyperpolarised than other C-nociceptors due to their TREK2; they express GFRα1. GDNF acts via GFRα1 to upregulate TREK2 and Nav1.9. Their slower CVs are correlated with higher Nav1.9 expression. The Aδ-HTMR/type II and more slowly conducting Aβ-nociceptors are mostly strongly trkA+(red). They show decreasing trkA-expression (pink) with increased CV to no trkA (white) in those with fastest CVs especially the Aβ-MPRs. (b) Likely nociceptor types in relation to CV >1 m/s are noted, with colour of writing relating to trkA+ or IB4+ expressions. CH have slowest CV. CMHs and some CMs are IB4+/Mrgprd+ (blue). CMiHi neurons may include IB4+ and trkA+ neurons, but this is not certain (Sections: Unresponsive neurons, CMiHi, silent or unresponsive-neurons), hence the question marks. (c) RF depths: In the epidermis, SC is stratum corneum; SG, stratum granulosum; SS, stratum spinosum; SB stratum basale. MrgprD+ (thus IB4+) fibers terminate in the stratum granulosum (SG), ∼10 μm from the keratin layer in mouse but not in deeper tissues. Their superficial termination sites are a likely/possible contributing factor to their low/variable thresholds (d). The few CGRP+ (thus trkA+) fibers in epidermis have RFs from stratum spinosum down to subcutaneous and deep. The MPRs have superficial RFs and those with fast CVs express little/no trkA, but some express trkC. (d) Nociceptive thresholds and the range of mechanical stimulus intensities that are encoded by firing rates, in relation to RF depths in C and CVs shown in (a). Thresholds of CPMNs and Aβ-MPRs tend to be lower than for most trkA+ HTMRs, shown in the middle as higher. Unlike LTMRs, they encode stimulus intensity through the noxious range. Thus on the left are slowly conducting IB4+/Mrgprd+ CPMNs and on the right, the fastest conducting cutaneous nociceptors, the MPRs. Both have low/no trkA-expression, superficial RFs and generally lower mechanical thresholds than trkA+ HTMRs.

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References

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