In microneurography experiments 56 unmyelinated nerve fibers were studied in the cutaneous branch of the peroneal nerve of healthy volunteers. Units were identified with the "marking" technique as mechanically and heat-responsive (CMH; n ϭ 30), heat-responsive (CH; n ϭ 13), or unresponsive to mechanical and heat stimulation (CM i H i ; n ϭ 13). None of the units showed spontaneous activity.These units were tested for responsiveness to iontophoresis of histamine (1 mA, 20 sec) from a small probe (diameter, 6 mm), which induced itch sensations lasting several minutes. Twenty-three units were unresponsive to histamine, and 25 units responded weakly with a few spike discharges after iontophoresis.Eight units, however, responded with sustained discharges to histamine, and their discharge patterns were matching the time course of the itch sensations. All C-units in this group were mechanically insensitive, and five of them were heat-responsive. They had very low conduction velocities of only 0.5 m/sec, on average, which is significantly lower than conduction velocities of the "polymodal" CMH units. This slow conduction velocities attributable to small axon diameters may be one reason why these units have not been encountered in previous studies. Histaminesensitive C-units had very large innervation territories extending up to a diameter of 85 mm on the lower leg.We conclude that these C-fibers represent a new class of afferent nerve fibers with particularly thin axons but excessive terminal branching. This type of C-fiber probably represents the afferent units long searched for mediating itch sensations.

Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E(2) (PGE(2)) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMi(His-)), and 24 mechanoinsensitive, histamine-positive (CMi(His+)) units were compared. CMi(His+) units were most responsive to histamine and to PGE(2) and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi(His-) units showed significantly weaker responses to histamine, PGE(2), and acetylcholine. Capsaicin and bradykinin responses were not significantly different in the two classes of mechano-insensitive units. We conclude that CMi(His+) units are "selective," but not "specific" for pruritogenic substances and that the pruritic potency of a mediator increases with its ability to activate CMi(His+) units but decreases with activation of CMH and CMi(His-) units.

One hundred ninety-four cutaneous C-fibers were recorded from the human peroneal nerve; 118 units were found by mechanical stimuli and 76 units were detected by electrical stimulation through a surface electrode. Needle electrodes were then inserted for electrical intradermal stimulation in the innervation territory of the units. Afferent and efferent sympathetic C-fibers were identified by slowing of conduction velocity after activation either by physical or chemical skin stimuli, or by arousal maneuvers eliciting sympathetic reflexes. In addition to mechano-heat-responsive C units (CMH) also found in previous studies, we here report on novel classes of C nociceptors in human skin, namely, units responding only to mechanical stimuli (CM), units responding only to heating (CH), and units that were insensitive to mechanical and heating stimuli and also to sympathetic provocation tests (CMiHi). With the electrical search technique we found 45% CMH, 13% CM, 6% CH, 24% CMiHi, and 12% sympathetic units. Excitation by topically applied mustard oil occurred in 58% of CMH units, and in one-third of CM and CMiHi units, respectively. Some CM, CH, and CMiHi units were sensitized to heating and/or to mechanical stimuli after topical application of mustard oil or capsaicin. These units then acquired responsiveness to a stimulus modality to which they previously were insensitive. Such recruitment of previously silent nociceptors implies spatial summation to the nociceptive barrage at central levels, and may contribute both to primary hyperalgesia to heat and pressure after chemical irritation, and to secondary hyperalgesia as a consequence of central sensitization.

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 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.

Axon reflex vasodilatation due to transcutaneous electrical stimulation in human skin was measured by laser Doppler imaging. Constant current pulses of 10 mA, 0.2 ms, delivered at 1 or 10 Hz for 2 min through a probe of 30 mm2 surface area did not induce a significant flare response, though this stimulus previously has been found supra-maximal for cutaneous polymodal (mechano-heat responsive) C-nociceptors in microneurography experiments. Pulses of the same strength from a pointed probe yielding a higher current density induced an extended and persistent flare. This type of stimulus previously has been proven to recruit mechano-insensitive C-units in microneurography experiments, in contrast to stimuli from the 30 mm2 probe. It is concluded that mechano-insensitive C-nociceptors and not polymodal C-units mediate the axon reflex flare in human skin.