Sensory neuron-expressed TRPC3 mediates acute and chronic itch

Area of Science:

• Neuroscience
• Immunology
• Dermatology

Background:

• Chronic pruritus, a key symptom of allergic contact dermatitis (ACD), lacks effective treatments due to poorly understood mechanisms.
• Transient Receptor Potential Canonical 3 (TRPC3) channels in sensory neurons are implicated in pain and itch signaling, but their specific role in chronic itch remains unclear.

Purpose of the Study:

• To investigate the role of TRPC3 channels in primary sensory neurons in the development of acute and chronic itch, particularly in the context of ACD.
• To explore TRPC3 as a potential therapeutic target for alleviating chronic itch associated with inflammatory skin conditions.

Main Methods:

• Examined Trpc3 mRNA expression in mouse trigeminal ganglion (TG) neurons.
• Utilized TRPC3 agonists and genetic deletion (global and conditional knockout) in mouse models.
• Assessed itch-like behaviors (scratching) and inflammatory responses in a murine contact hypersensitivity (CHS) model.

Main Results:

• Trpc3 is predominantly expressed in nonpeptidergic, small-diameter TG neurons, many of which are involved in itch sensing.
• TRPC3 activation induced neuronal activation and acute itch- and pain-like behaviors; Trpc3 deletion attenuated itch from specific pruritogens.
• In the CHS model, TRPC3 expression and function were upregulated; TRPC3 inhibition or knockout significantly reduced scratching without altering skin inflammation.

Conclusions:

• TRPC3 channels in primary sensory neurons contribute to both acute and chronic itch, independent of histamine signaling.
• Targeting neuronal TRPC3 presents a promising therapeutic strategy for managing chronic itch in ACD and other inflammatory skin disorders.