EFFECT OF NOXIOUS HEAT STIMULUS IN THE PERCEPTION OF NON-HISTAMINERGIC ITCH

Background & Aims

Chronic itch is a symptom of many pathological conditions. Optimal treatments are lacking mostly due to the limited knowledge of the phenomenon. Itch follows two different pathways: histaminergic (transmitted by mechano-insensitive C-fibers) and non-histaminergic (conveyed by polymodal C-fibers), respectively activated in experimental models by histamine and cowhage 1. Itch and pain share many similarities in terms of mechanisms and molecules involved, and over the years many theories have been suggested to explain how the itch signals are transmitted from the skin, where it is perceived, to the brain 2. The phenomenon that pain inhibits pain is a well-known mechanism 3, but it is not known if pain is inhibiting itch 4,5. In this context, this experiment aims to investigate the extent to which thermal short cutaneous pain stimulation can affect itch perception and the differences in itch perception when the painful stimulation is applied on the same forearm versus the opposite forearm.

Methods

20 participants were recruited in this pilot study. In the 1st session, one area (4×4 cm) was selected on the subjects’ forearm and treated with cowhage. During the application of the substance, participants continuously rated itch and pain intensities for 9 minutes on a VAS scale from 0 (no itch/pain) to 10 (worst imaginable itch/pain). In the 2nd session (one day after), one area on each forearm was selected. Cowhage was applied on the same area as the 1st session, and itch and pain ratings were collected for 9 minutes. At the same time, the other area was exposed to thermal pain (46.5 °C), which starts 60 seconds after the cowhage application and lasts for two minutes. After cowhage removal, participants were asked to retrospectively rate the pain intensity of thermal stimulus on an NRS scale from 0 (no pain) to 10 (worst imaginable pain). The 3rd session was the same as the 2nd one, with the two areas on the same arm. The order of the 2nd and 3rd sessions was randomized.

Results

The 3 conditions analyzed were: cowhage alone, cowhage + heat stimulus in the same arm (C+H SA), and cowhage + heat stimulus in different arms (C+H DA).
The area under the curve (AUC) of itch was lower in the C+H SA compared to cowhage (p<0.05), while no differences were observed for the peak itch intensity (p=0.111). Looking at the temporal profile graph, it is possible to observe how the itch intensity induced by cowhage instantly decreased when the heat stimulus was applied, in both C+H SA and DA. Similar results were obtained by the analysis of pain intensity. An overall difference was found in AUC pain (p<0.05). After a postdoc analysis, C+H SA and DA showed a tendency to be lower than cowhage (p=0.053, p=0.054 respectively). No differences were observed in peak pain intensity (p=0.14). As shown in the temporal profile graph, the application of the heat stimulus induced a reduction in pain perception in C+H SA and DA conditions.

Conclusions

The present pilot study seems to confirm the idea that pain inhibits itch. This mechanism was particularly evident when the pain stimulus was applied in the same arm of itch provocation. These results possibly confirm the selectivity hypothesis postulating that itch perception occurs when the itch-selective fibers are activated without significant co-activation of pain fibers. Moreover, cowhage application induced pain besides itch, and this pain component was reduced by the noxious stimulus.
More studies are needed to better understand how pain influences the itch sensation.

References

1.Andersen, H. H. & Arendt-Nielsen, L. Human Surrogate Models of Itch and Pain. in Itch and Pain: Similarities, Interactions, and Differences (2020).
2.Carstens, E., Carstens, M. I. & Follansbee, T. Coding of itch and pain: neurophysiological parallels and differences. in Itch and Pain: Similarities, Interactions, and Differences (Wolters Kluwer, 2020).
3.Youssef, A. M., Macefield, V. G. & Henderson, L. A. Pain inhibits pain; human brainstem mechanisms. Neuroimage 124, 54–62 (2016).
4.Andersen, H. H., van Laarhoven, A. I. M., Elberling, J. & Arendt-Nielsen, L. Modulation of itch by conditioning itch and pain stimulation in healthy humans. J Pain 18, 1437–1450 (2017).
5.Andersen, H. H., Yosipovitch, G. & Arendt-Nielsen, L. Pain inhibits itch, but not in atopic dermatitis? Annals of Allergy, Asthma & Immunology 120, 548–549 (2018).