Journal Club 18.05.04.

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons
Radhika Palkar1,3, Serra Ongun1,2, Edward Catich1,3, Natalie Li1, Neil Borad1, Angela Sarkisian1 and David D. McKemy1,2,3

1Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California; 2Molecular and Computational Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California; and 3Neuroscience Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California
Correspondence: David D. McKemy, Neurobiology Section, Department of Biological Sciences, University of Southern California, 3641 Watt Way, HNB 201, Los Angeles, CA 90089. E-mail: mckemy@dornsife.usc.edu
Abbreviations: Cqx, chloroquine; a-Me5-HT, a-methyl 5-HT
Received 16 August 2017; revised 8 December 2017; accepted 20 December 2017; accepted manuscript published online 27 December 2017; corrected proof published online XXX

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter-stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch.
Journal of Investigative Dermatology (2018) -, -e-; doi:10.1016/j.jid.2017.12.025