INVESTIGATIVE REPORT
855 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Modulation of Itch by Localized Skin Warming and Cooling
Kristen M. SANDERS, Takashi HASHIMOTO, Kent SAKAI and Tasuku AKIYAMA Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA
Skin thermal changes modulate itch sensitivity. However, the mechanisms of this modulation are still unclear. Using mouse models of acute and chronic itch, we investigated whether local innocuous thermal stimulation of the skin alters itch sensitivity and if blockade of thermosensitive transient receptor potential( TRP) channels can reduce these changes. Localized thermal changes were achieved by placing a thermal probe in contact with the back skin for 30 s. Warming the skin significantly increased serotoninevoked scratching and spontaneous scratching in the ovalbumin model of atopic dermatitis but decreased histamine-evoked scratching. These changes were blocked by a TRPV4 antagonist. Cooling the skin significantly increased serotonin-evoked scratching but reduced histamine-evoked scratching. The increase in serotonin-evoked scratching, but not the reduction of histamine-evoked scratching, was blocked by TRPM8 antagonism. Chloroquine-evoked scratching was unaffected by either warming or cooling. Our data indicate that different itch signaling pathways are differentially modulated by skin thermal changes.
Key words: temperature; chronic itch; atopic dermatitis; scratching; TRPV4; TRPM8.
Accepted Jun 5, 2018; Epub ahead of print Jun 8, 2018 Acta Derm Venereol 2018; 98: 855 – 861.
Corr: Tasuku Akiyama, PhD, Department of Dermatology and Cutaneous Surgery, Miami Itch Center, University of Miami, 1600 NW 10th Ave RMSB2063, Miami, FL 33136, USA. E-mail: takiyama @ miami. edu
The perception of itch is modulated by skin temperature as affected either by the environment or by experimental local change. Human psychophysical studies consistently show that noxious thermal stimulation reduces histamine- and cowhage-evoked itch and spontaneous itch in patients with atopic dermatitis( AD)( 1 – 6). Such noxious counter-stimulation can reduce itch when applied distally or contralaterally to the site of itch induction( 1, 3, 7) and activates the periaqueductal gray, the control center for descending pain modulation( 8). These results suggest that endogenous central inhibitory systems play a major role in the antipruritic effects of counter-stimulation. However, there has been comparatively limited research in the effects of innocuous thermal stimuli on itch and whether these stimuli are sufficient to drive central inhibitory systems.
Most human studies of innocuous temperature modulation of itch have been conducted using histamine. Innocuous cold stimulation has repeatedly been shown
SIGNIFICANCE
Many people report that temperature changes can increase or decrease itch. This study tests how gentle warm and cool temperature stimulation affects itch from 3 different chemicals and one atopic dermatitis model. Warming and cooling the skin decreased scratching in mice that received histamine but increased scratching from serotonin. Neither temperature change affected scratching from chloroquine. In the atopic dermatitis model, warming the skin increased scratching, and cooling slightly delayed scratching. In some cases, but not all, temperature-sensitive channels were involved in these effects. This study reveals that gentle temperature modulation of itch is complex and may involve multiple pathways.
to significantly reduce histamine-evoked itch( 1, 2, 9). In one study, innocuous warmth was reported to reduce histamine-evoked itch in a majority of subjects, but not all( 4). Other studies consistently show an insignificant decrease in histamine-evoked itch by warming the skin( 1 – 3). However, most types of chronic itch are not mediated by histamine, and thermal modulation appears to have different effects in the chronic itch state. As with histamine-induced itch, cooling of the skin is commonly reported to alleviate itch in AD( 10, 11). In contrast, questionnaire data from patients with AD show that warmth is one of the major aggravating factors for itch in this disease( 12, 13).
Itch is mediated by multiple neural pathways( 14 – 17). Histamine, mainly released from mast cells and basophils in the skin, evokes itch through histamine receptors H1R and H4R( 18). Chloroquine, an anti-malarial drug which activates Mas-related G protein-coupled receptor member A3, induces acute itch through a non-histaminergic pathway( 19). Another histamine-independent itch mediator, serotonin, is released by platelets and activates 5-hydroxytryptamine type 2( 5-HT2) and 5-HT7 receptors to induce non-histaminergic itch( 20, 21). Interestingly, serotonin-evoked itch, but not chloroquine-evoked itch, is enhanced by ambient warm temperature( 22), implying that the effect of temperature on itch intensity differs among different types of pruritogens. However, the effects of temperature on different types of itch, especially histamine-independent itch, are poorly understood.
One possibility is that innocuous temperature changes modulate skin perfusion and thereby alter the concentration and distribution of pruritogens. While local cooling of the skin causes a localized vasoconstriction, local warming of the skin causes a localized vasodilation( 23,
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2990 Acta Derm Venereol 2018; 98: 855 – 861