Mechanisms of Pruritogen-Induced Activation of Itch Nerves in Isolated Mouse Skin

Ru, F1., Sun, H1., Jurcakova, D.1,3, Herbstsomer, R.A1., Meixong, J2., Dong, X2, Undem, B.J. 1
Departments of Medicine1 and Neuroscience2, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 3Department of Pathophysiology, Biomedical Center Martin, Jessenius Medical School, Comenius University, Martin, Slovakia

Running Title: Characterization of itch causing nerves

Mechanisms of Pruritogen-Induced Activation of Itch Nerves in Isolated Mouse Skin

Key Points Summary
Chloroquine (CQ) stimulates itch nerves and causes intense scratching in mice by activating the G- Protein Coupled Receptor (GPCR) MrgprA3. It is not known how stimulation of MrgprA3 (or other GPCRs) leads to activation of the itch nerve terminals in the skin, but previous studies have found that TRPA1 gene deletion blocks CQ-induced scratching.
In the present study we used a novel dorsal skin-nerve preparation to evaluate mechanisms underlying CQ- and histamine-induced action potential discharge in itch nerve terminals.
We found that CQ activation of the nerves requires the beta3 isoform of phospholipase C, however, TRPA1 or other TRP channel are not required. Evidence is provided for a role for calcium-activated chloride channels such as TMEM16a in GPCR-activation of itch nerve terminals.
The mechanism by which TRP channels participate in pruritogen-induced scratching may involve sites of action other than the primary afferent terminals.