Fig. 9

Shows a mechanistic illustration of different itch theories related to our results. A From top to bottom is shown: spatial contrast theory, population coding theory and temporal discharge pattern theory. For each theory, a skin section (Epidermis, Dermis) is shown for itch and pain and illustrated by the bar above with the overlapping gradient from pain (red) to itch (green). The activation pattern of the free nerve endings in the skin (CM-fibers: blue; CMi-fibers: red and A-fibers: black) is shown in the colour of the respective fiber typ. (1) Spatial contrast theory: activation of major C-fibers leads to pain; highly activated C-fibers in contrast to silent C-fibers leads to itch (injection vs. focal). (2) Population coding: The activation of CM- and CMi-fibers leads to pain; the activation of A-fibers and/or the lack of CMi-fibers activation leads to itch. (3) Temporal discharge pattern: no bursting discharge in CM-fibers leads to pain and bursting discharge in CM-fibers leads to itch. B Combinations of different itch and pain signaling theories potentially explaining the effect of the non-histaminergic pruritogens β-alanine, BAM 8-22 and cowhage. C The proximity of substances to the different theories (in the corners) shows, based on our results, the applicability of that theory.