Chronic itch that induces scratching is a defining symptom for AD6. Pro-inflammatory cytokines from T cells and keratinocytes are considered as a key factor in the pathogenesis of AD and atopic itch11. Immunosuppressants and corticosteroids are known to reduce inflammatory components of AD and the resulting itch5. These treatment modalities are not effective for every patient with AD because they fail to target the substantial neural component of the pathophysiology of the itch. Therefore, there is a need for alternative treatments that can directly target neural pathways or intersection between nerves, immune cells, and keratinocytes17.
Localized skin warming and cooling therapies are believed to be alternative therapeutic modalities that can help relieve the itchy sensation in patients with AD. Additionally, it is known that various itch signaling pathways are differentially modulated by changes in skin temperature 14. Changes in skin temperature have a marked influence on the intensity of pruritus5. In particular, skin cooling is an effective temporary remedy that relieves pruritus in various itchy dermatologic disorders including AD9. Cooling can reduce nerve excitability and conduction velocity as well as slow the biochemical mechanisms essential for neurotransmission and neuropeptide release, such as those in itch-mediating C-fibers2. In addition, cutaneous vasoconstriction caused by cooling can reduce the release of pruritus-inducing substances3.
Previous studies have reported that TRPA1, TRPV1, TRPM8, and PAR2 are all involved in the pathogenesis of the itch mechanism11,16. The TRP superfamily is known as a major component of the mechanisms of various sensory perceptions including that of itch10. Six channels are known to play a regulatory role regarding the thermal/mechanical/chemical transmission in the skin. TRPV-1, -2, -3, and − 4 are referred to as “heat channels,” while TRPM8 and TRPA1 are referred to as “cold channels”15. Among them, TRPV1, TRPA1, and TRPM8 are expressed in human skin and have been associated with itch. Sander et al.14 reported that 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.
Interleukin (IL)-2, IL-4, IL-13, and IL-31 used in this experiment are various cytokines and chemokines that have been reported to be correlated with chronic pruritus11. In particular, IL-31 is a T helper (Th) 2 cell-derived cytokine that appears to play a critical role in pruritus in AD and is emerging as a new therapeutic target12. Systemic and local administration of IL‐31 induces itching and scratching in mammals, including humans, probably in a dose‐dependent manner4.
This study was performed to evaluate the possible antipruritic effects of different cooling stimulations at temperatures from − 5°C to 5°C by comparing the expression of gene and protein levels associated with itching and inflammation in a mouse model. In general, it showed that cold temperatures downregulated the expression of itch-related biomarkers at the gene and protein level. According to the temperature and duration of treatments used in the study, the degree of statically significant decrease was different for each biomarker.
In conclusion, these studies have shown that cryotherapy is effective for decreasing pruritus in the AD mouse model, particularly at certain temperatures and durations, resulting in the reduction of itch-related biomarkers.
Furthermore, this study demonstrates the pruritus-relieving effect of the temperature-adjustable device for mice. This may provide some evidence for future studies on patients with mild AD, which may become an opportunity to consider its use as an alternative treatment for chronic itch.