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Nat Med. 2018 Aug;24(8):1268-1276. doi: 10.1038/s41591-018-0083-x. Epub 2018 Jul 9.

Anatomical and functional dichotomy of ocular itch and pain.

Author information

1
Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA.
2
Merck Research Laboratories, South San Francisco, CA, USA.
3
Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
4
Department of Anesthesiology and Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
5
School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Jiangsu, China.
6
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
7
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
8
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
9
Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA. qinliu@wustl.edu.
10
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA. qinliu@wustl.edu.

Abstract

Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.

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