Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin

Abstract

Microneurography was used in healthy human subjects to record action potentials from unmyelinated nerve fibers (C units) in cutaneous fascicles of the peroneal nerve. Activity-dependent slowing (n = 96) and transcutaneous electrical thresholds (n = 67) were determined. Eight units were sympathetic efferents according to their responses to sympathetic reflex provocations. Mechano-heat-responsive C units (CMH) (n = 56) had thresholds to von Frey hair stimulation </=90 mN (6.5 bar). Mechano-insensitive C units (n = 32) were unresponsive to 750 mN (18 bar). Twenty-six mechano-insensitive units responded to heat (CH), and the remaining six units did not respond to physical stimuli but were proven to be afferent by their response to intracutaneous capsaicin (CM(i)H(i)). Mechano-insensitive units had significantly slower conduction velocity (0.81 +/- 0.03 m/sec), and CH units had higher heat thresholds (48.0 +/- 0.6 degrees C) compared with CMH units (1.01 +/- 0.01 m/sec; 40.7 +/- 0.4 degrees C). Transcutaneous electrical thresholds were <9 mA for CMH units and >35 mA for CH and CM(i)H(i) units. Activity-dependent slowing was much more pronounced in mechano-insensitive than in mechano-responsive units, without overlap. Sympathetic efferent C units showed intermediate slowing, significantly different from CMH, and completely separate from CH and CM(i)H(i) units. The activity-dependent slowing of conduction provides evidence for different membrane attributes of different classes of C fibers in humans.

Figures

Fig. 1.

Conduction velocity and electrical thresholds. Transcutaneous electrical thresholds were assessed with a surface electrode designed for homogeneous current application. Forty-six CMHs (open squares), 16 CHs (filled circles), and five CMiHis (open circles) were tested. The difference between transcutaneous electrical thresholds of mechano-responsive (squares) and mechano-insensitive (circles) units was highly significant. Within each category of units, no significant correlations between conduction velocities and transcutaneous electrical thresholds were found.

Fig. 2.

Slowing of conduction velocity during repetitive stimulation. Specimen obtained during the electrical stimulation protocol applied to a group of five C units recorded simultaneously. After a 2 min recovery period, the nerve terminals were stimulated by intracutaneous impulses at 0.125, 0.25, and 0.5 Hz and then again at 0.25 Hz. Subsequent traces are shown from top tobottom. The toptraceprovides an amplified and unfiltered view of the recording also shown in the first trace of the following sequence. For the standard protocol, 20 stimuli were applied at 0.125 and 0.25 Hz, and 30 stimuli at 0.5 Hz. In this specimen record, only 20 stimuli at 0.5 Hz are shown. In the bottom, responses of the five units to mechanical stimulation with a stiff von Frey bristle are shown (750 mN;arrow). Unit (b) was mechano-insensitive. Units (a, c–e) showed pronounced marking responses to mechanical stimulation.

Fig. 3.

Slowing in three categories of C-fibers. Latency increases (mean ± SEM) induced by 20 impulses at 0.125 and 0.25 Hz and after 30 pulses at 0.5 Hz are shown separately for each frequency. Within the group of mechano-insensitive units (filled bars), values for CH and CMiHi are shown separately. There was no statistically significant difference between the two subgroups of mechano-insensitive units. Slowing differed significantly between the CMH, sympathetic, and CH/CMiHi unit categories. Statistical differences were assessed by unpaired t tests; *p < 0.05; **p < 0.01.

Fig. 4.

Thresholds of afferent units and total slowing. Heat (A), mechanical (B), and transcutaneous electrical thresholds (C) are all plotted against total slowing (sum of latency increases during application of all three stimulus frequencies). Mechano-insensitive units (filled circles) did not respond to von Frey filament stimulation (750 mN), and hence no mechanical thresholds are shown for this category. Heat thresholds were higher in mechano-insensitive units (p < 0.001; unpaired t test) but did overlap between the two classes. In contrast, electrical thresholds separated both nociceptor classes completely. Within the categories of mechano-responsive (open squares) and mechano-insensitive units, none of the threshold values showed significant correlations with total slowing apart from a low positive correlation between total slowing and mechanical thresholds (p = 0.05;B).

Fig. 5.

Total slowing from the three categories of C units plotted versus conduction velocities. The two afferent classes of mechano-responsive and mechano-insensitive units formed two separate clusters (dotted line), but there was no clear separation between mechano-responsive and sympathetic units.