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