The Ion Channel TRPA1 Is Required for Chronic Itch

Abstract

Chronic itch is a debilitating condition that affects one in 10 people. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. We demonstrate that the ion channel TRPA1 is required for chronic itch. Using a mouse model of chronic itch, we show that scratching evoked by impaired skin barrier is abolished in TRPA1-deficient animals. This model recapitulates many of the pathophysiological hallmarks of chronic itch that are observed in prevalent human diseases such as atopic dermatitis and psoriasis, including robust scratching, extensive epidermal hyperplasia, and dramatic changes in gene expression in sensory neurons and skin. Remarkably, TRPA1 is required for both transduction of chronic itch signals to the CNS and for the dramatic skin changes triggered by dry-skin-evoked itch and scratching. These data suggest that TRPA1 regulates both itch transduction and pathophysiological changes in the skin that promote chronic itch.

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Comprehensive gene expression-profiling analyses in mouse models of chronic itch (alcohol-ether-water dry skin) reveal that TRPA1 activity is a key mediator of chronic itch phenotypes. TRPA1 activity induces expression changes in many genes contributing to scratch behavior, dermatitis, dry skin, and other sensory, inflammatory, or immune responses (Wilson et al, 2013a). This study also highlighted a potential role for TRPA1 in itch hypersensitivity incurred through increases in the expression of itch receptors (e.g., B 2 R) and innervation by itch-detecting primary afferent nerve fibers, as previously observed in dry skin mouse models .…”

Mouse Monoclonal Antibodies to Transient Receptor Potential Ankyrin 1 Act as Antagonists of Multiple Modes of Channel Activation

“…In agreement with this hypothesis, it was reported that the endogenous aldehyde 4-hydroxynonenal (4-HNE) causes pain and neurogenic inflammation through activation of TRPA1 (Trevisani et al, 2007). Furthermore, a number of studies also suggested that TRPA1 plays a role in itch (Wilson et al, 2011(Wilson et al, , 2013 as well as cough and asthma (Taylor-Clark et al, 2009;Viana and Ferrer-Montiel, 2009;Geppetti et al, 2010).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Urushiol, the contact allergen in poison ivy, evokes pruritogenic responses in wild-type, but not in TRPA1-null, mice . Chronic itch evoked by impaired skin barrier is also attenuated in the TRPA1-deficient animals (Wilson et al, 2013a). TRPV1 as an itch target is more problematic.…”

“…Recent data implicate TRPA1 as the primary itch mediator in atopic dermatitis Wilson et al, 2013a,b). Diseased (atopic dermatitis) keratinocytes release thymic stromal lymphopoietin (TSLP) via the Recent data implicate TRPA1 as the primary itch mediator in atopic dermatitis Wilson et al, 2013a). Diseased atopic dermatitis keratinocytes release thymic stromal lymphopoietin (TSLP) via the ORAI1/NFAT pathway; in turn, TSLP activates TRPA1-expressing cutaneous afferents to trigger itch (Wilson et al, 2013b).…”