Sensory neuron–expressed TRPC3 mediates acute and chronic itch

Abstract

Background: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proin ammatory mediators. However, the role of TRPC3 in acute and chronic itch is still not well de ned.Methods: RNAscope in situ hybridization and immunohistochemical staining were performed on mouse trigeminal ganglion (TG) neurons. Fura-2 calcium imaging was used to characterize the function of TRPC3 in dissociated TG neurons. In native mice, the TRPC3 agonist and pruritogens were subcutaneously injected to the cheek and nape of the neck of mice, respectively. Site directed scratching and/or wiping behaviors were video recorded.Contact hypersensitivity (CHS) model was induced in mouse ears by topical application of SADBE or DNCB. Spontaneous scratching behaviors were recorded by video monitoring. Global and conditional Trpc3 knockout mice were employed to determine the contribution of TRPC3 to acute and chronic itch. The mRNA expression levels of Trpc3 and proin ammatory cytokines were assayed by quantitative realtime PCR. H&E. staining was used for the evaluation of the thickness of mouse ears. Flow cytometry was performed to assess immune cell in ltration in mouse ear tissues.Results: Among mouse TG neurons, RNAscope assay revealed that Trpc3 mRNA was predominantly expressed in nonpeptidergic small diameter neurons. Moreover, Trpc3 mRNA signal was present in the majority of itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH 2 . In a murine model of CHS, Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 signi cantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous in ammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model.Conclusions: These ndings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might bene t the treatment of chronic itch associated with ACD and other in ammatory skin disorders.

Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice

“…47 Transient receptor potential (TRP) channels, such as TRPA1, TRPV1, TRPV4, and TRPC3, are required for the induction of both pain and itch. 8,14,20,50,52,54,60,86 Limited studies have shown that SPMs alleviate itch by peripheral mechanisms, such as reducing skin inflammation and modulation of TRP channels. Resolvin E1 attenuates murine psoriatic dermatitis, a chronic itch disease, by inhibiting migration of cutaneous dendritic cells and gd T cells.…”

The G protein‐coupled estrogen receptor of the trigeminal ganglion regulates acute and chronic itch in mice

“…Images were acquired using an inverted fluorescence microscope system (DMI8, Leica) with alternating excitation wavelengths of 340 and 380 nm. The 340 nm/380 nm fluorescence intensity ratio [ R (340/380)], measured with the PCI software every 2 s, was applied as an intracellular calcium concentration ([Ca 2+ ]i) indicator 40 . If the increase in [ R (340/380)] was equal to or greater than 15% of baseline, neurons were considered to be responsive to a particular chemical stimulus.…”

Transient Receptor Potential Channels and Itch

“…One study found that TRPC3 agonism induced histamine-independent itch and TRPC3 knockout mice had significantly decreased spontaneous scratching behaviors. Additional research is needed on the therapeutic benefits of targeting TRPC channels [61].…”