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.