Specific C-receptors for itch in human skin

Abstract

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 = 30), heat-responsive (CH; n = 13), or unresponsive to mechanical and heat stimulation (CMiHi; n = 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. Histamine-sensitive 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.

Fig. 1.

Top, Instantaneous discharge frequency of a mechanically and heat-insensitive C-fiber (CM_iH_i) in the superficial peroneal nerve after histamine iontophoresis (gray bar). The unit was not spontaneously active before histamine application but continued to fire for a few minutes after termination of the plot.Bottom, Average itch magnitude ratings of a group of 21 healthy volunteers after an identical histamine stimulus. Ratings were at 10 sec intervals on a VAS with the end points no itch and unbearable itch. Error bars indicate SE.

Fig. 2.

Left panel, Responses of a CM_iH_i unit (mechanically and heat-insensitive C-fiber) to histamine iontophoresis are demonstrated with the marking technique. Subsequent spike responses to electrical stimulation at 4 sec intervals are shown from top tobottom. Bold spikes are from the unit under study. Histamine iontophoresis is marked at the upper left corner. Activation of the unit is represented as a deviation of the spike trail to the right. Right panel, The spike trails of two mechanically and heat-responsive (CMH) units are shown, which were simultaneously recorded in another experiment. Both units were excited by the iontophoresis current (marked at left), but only unit (a) shows a weak histamine response.

Fig. 3.

Summary of histamine responses in different classes of C-fibers. Activity after histamine iontophoresis is represented as number of activation periods, i.e., stimulus cycles in which marking occurred. The three columns to theleft represent units that did not respond at all to histamine. The eight units with more than 40 activation periods showed sustained responses.

Fig. 4.

Conduction velocities, depicted on theordinate, of C-fibers differentiated in classes according to their responsiveness to mechanical and heat stimulation (CMH, CH, and CM_iH_i) and according to their insensitivity, weak sensitivity, and sustained responses to histamine. Units with sustained responses to histamine have significantly lower conduction velocities.

Fig. 5.

Transcutaneous excitation and distribution of histamine-sensitive spots of histamine-sensitive C-fibers labeled1–8. Black areas represent spots from which the respective unit was excited by transcutaneous stimulation.Circles with crosses, Histamine iontophoresis leading to excitation. Open circles, Unresponded histamine iontophoresis. Locations of the innervation territories are shown on the schematic leg on theright.