Spatial and Temporal Summation of Histaminergic and Non-Histaminergic Itch

Chronic itch represents a social burden due to its high prevalence, negative impact on quality of life, and limited treatment options. Spatial (simultaneously applied stimuli at multiple skin sites) and temporal (repeated stimuli over time) summation are key mechanisms in itch processing but have not been investigated in detail in humans. This study assessed experimentally induced histaminergic and non-histaminergic itch provocations in healthy volunteers. In the spatial summation experiment, histamine or cowhage was applied in randomized order to one area, two areas on the same arm, or two areas on different arms. Itch and pain intensities were recorded for 9 min, followed by assessment of alloknesis and hyperknesis. In the temporal summation experiment, each pruritogen was applied either once or repeatedly at intervals of 90 or 180 s apart to the forearm. Itch and pain intensities were recorded for 15 min, after which superficial blood perfusion (SBP), alloknesis, and hyperknesis were assessed. Itch intensity and calculated area under the curve (AUC) were significantly facilitated by special summation after both ipsilateral and contralateral applications of both pruritogens. Temporal summation significantly increased AUC after reapplication of either of the pruritogens after 180 s. Reapplication after 90 s significantly increased cowhage-induced SBP, while reapplication after 180 s increased histamine-induced SBP. In conclusion, spatial summation augmented itch intensity and AUC, whereas temporal summation increased AUC and enhanced SBP. Both effects were observed for histaminergic and non-histaminergic itch, highlighting differences in fundamental mechanisms.