Abstract
Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.
Highlights
Itching is a common somatic sensation that is distinct from other senses, such as temperature, touch, and pain (Davidson and Giesler, 2010)
We aimed to explore the role of Zn2+ in the regulation of acute and chronic itch
We found that both exogenous and endogenous Zn2+ were critically involved in the pathogenesis of acute and chronic itch in mice
Summary
Itching (pruritus) is a common somatic sensation that is distinct from other senses, such as temperature, touch, and pain (Davidson and Giesler, 2010). According to the duration, itching is divided into acute itch and chronic itch. Acute itch lasts several minutes to days and serves as an alarm system to remove the potential harmful stimulation from the body (Pfab et al, 2012). Chronic itch lasts for more than 6 weeks and is a common symptom of many diseases (Sakai et al, 2016; Andersen et al, 2017), including skin diseases, cholestasis, chronic kidney diseases (Mettang and Kremer, 2015; Cheng et al, 2019; Patel et al, 2019), neurological diseases (Misery et al, 2014), some cancer, and mental illness (Misery et al, 2018). Identification of novel itch mediators and related signaling pathways is helpful for understanding the mechanisms underlying chronic itch but may lead to developing new effective anti-itch therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
